Munc13-1在小鼠胰岛素分泌调控中的作用机制研究
摘要
胰腺β细胞在葡萄糖刺激下表现典型的双相分泌反应,完全的双相分泌是健康β细胞的标志,糖尿病伴随着胰岛素双相分泌的受损。40多年来,胰岛素双相分泌的细胞生物学基础一直存在很大的争议。一般认为胰岛素的双相分泌对应于不同类型的囊泡库,已锚定和成熟的囊泡(RRP)对应于第一相分泌,而可释放囊泡的补充则构成第二相分泌。但是双相分泌的产生是一个多因子参与的极其复杂的过程,进一步阐明其机理具有重要意义。Munc13是C. elegans Unc-13和Drosophila Dunc-13在哺乳动物中的同系物,有四种亚型,是SNARE蛋白的调节蛋白之一。Munc13-1/unc13基因敲除使神经突触不能形成RRP囊泡,从而使神经递质释放被完全阻断。Munc13蛋白含C2结构域和可与DAG结合的C1结构域。DAG/佛波醇结合到C1结构域增强了Munc13-1促囊泡成熟的能力,但是在内分泌LDCV囊泡上,Munc13的作用尚不清楚。本课题以Munc13-1基因敲除小鼠(KO)和Munc13-1H567K点突变小鼠(KI)为研究对象,系统研究了Munc13-1在胰岛素分泌及其在DAG信号调控过程中的作用。主要实验结果如下:
1) Munc13-1基因敲除小鼠出生后几个小时内死亡,我们发现培养2-3天的新生小鼠β细胞表现典型的成年小鼠β细胞特点,如Na+通道失活及对葡萄糖的响应等。本培养方法的成熟为以出生致死型基因敲除小鼠为模型研究胰岛素分泌的分子机制奠定了基础。
2)虽然Munc13-1在神经递质的释放过程中是不可缺少的因子,但它在内分泌大致密核心囊泡(LDCV)分泌的作用却尚不清楚。我们以膜电容检测和光解释钙技术相结合,发现在Munc13-1 KO小鼠中,延迟型组分的分泌几乎完全被抑制,KI小鼠中也明显降低。但是代表可释放囊泡分泌的簇发型分泌相却没有明显改变。连续去极化实验得到类似的结果,RRP排空后的恢复时间常数在KO小鼠中也明显延长。表明Munc13-1是胰岛素延迟相分泌所必需的,直接证明Munc13-1对长时程刺激下LDCV的补充起作用。由于Munc13-1的缺失使神经突触不能形成RRP囊泡,而在β细胞中却是正常的,说明Munc13-1在神经突触囊泡和LDCV的分泌中起着不同的作用。
3)胰岛素双相分泌的产生机理尚有待阐明,我们以ELISA检测Munc13-1基因敲除小鼠胰岛素分泌,发现Munc13-1缺失选择性抑制葡萄糖诱导的第二相分泌,直接证明了LDCV的成熟过程是第二相胰岛素分泌的限速步骤。
4)第二相分泌的产生或增强,需要代谢信号,而非膜去极化信号(通过KATP通道的关闭产生)的参与,然而具体参与的有哪些代谢信号还有待研究。我们对DAG接合能力缺失的Munc13-1H567K KI小鼠的研究表明葡萄糖诱导的DAG信号通路参与了胰岛素分泌的调控,Munc13-1是DAG/佛波醇通路一个关键的靶标分子。PMA能易化小鼠胰岛素的分泌,但KI小鼠中没有此效应,表明PKC不参与小鼠胰岛素分泌的调控,或作用于Munc13-1的上游。
Insulin release from pancreaticβcells in response to glucose is characterized by a biphasic time course. A full biphasic insulin response is the ultimate indication of a well-coupled healthyβcell. Interestingly, diabetes is associated with disturbance in the biphasic pattern of insulin secretion, resulting in a diminished first phase and a blunted second phase. Although first described almost 40 years ago, the cell biology of the two phase of insulin secretion remains debated. Thus it is of great importance to understand the mechanisms whereby the biphasic insulin response is generated and regulated. However, as the generation of biphasic insulin release probably involves concerted action of multi-factors, the significance of different functional LDCVs in the contribution of biphasic insulin release under glucose stimulation remains to be clarified. Munc13 proteins constitute a family of 4 mammalian homologues of C. elegans Unc-13 and Drosophila Dunc-13. Genetic deletion of Munc13-1/unc13 causes total arrest of synaptic transmission due to a complete loss of fusion-competent synaptic vesicles. Munc13 proteins contain C2 domain and a DAG binding C1 domain. The binding of DAG/phorbol-ester to C1 domain leads to enhanced priming activity of Munc13-1. The requirement of Munc13s for LDCVs, however, has not been established.
In the current study, we have aimed at elucidating the role of Munc13-1 in the insulin secretion and dissecting its site of action using Munc13-1 knockout and Munc13-1H567K knockin mice. Secretion was analyzed by a combination of capacitance and dynamic insulin release measurements. Main results of the study are as fellows.
1.Munc13-1-defecient mice die within a few hours of birth. Hence, we had to isolateβcells from newborn mice. we found isolatedβcells from newborn mice apparently developed typicalβcell characteristics including Na+ channel inactivation and response to glucose after 3 days in culture. The establishment of the experimental system will open possibility for elucidating the molecular mechanism of insulin secretion control using various knockout mice that are lethal at birth.
2. Although Munc13-1 is absolutely necessary for neurotransmitter release from synaptic vesicles, the requirement of Munc13-1 for large dense core vesicles (LDCVs) has not been demonstrated. Cm measurements combined with flash photolysis was employed to assess the exocytosis from different pools of LDCVs. We found that the sustained component of exocytosis was almost completely abolished in Munc13-1-deficientβcells, and to a lesser extent in KI cells. The exocytotic burst, which represents the releasable vesicles, was not significantly influenced. We thus conclude that Munc13-1 is required for the second phase of insulin secretion in response to glucose stimulation. This is the first evidence that Munc13-1 is required for the supply of LDCVs during prolonged stimulus. Whereas knockout of Munc13-1 causes complete loss of readily releasable synaptic vesicles, we found that readily releasable LDCVs are normal in Munc13-1-deficient beta cells. These results suggest different requirement of Munc13-1 for synaptic vesicles and LDCVs.
3. The mechanism underlying the generation of biphasic insulin response is elusive. The ultimate answer to this question would have to wait for the identification of molecular players that are specifically involved in the production of the biphasic insulin release. We now show that genetic ablation of Munc13-1 preferentially abolishes the second phase of insulin response to glucose, providing direct evidence that the priming of LDCVs from an unprimed pool constitutes the rate limiting step in the second phase of insulin release.
4. It has been demonstrated that metabolic signals, other than the membrane-depolarizing signal (generated by closing KATP channels), are required for the production (or amplification) of the second phase. However the identities of these signals remain to be identified. Our results showing that the sustained insulin release is impaired in DAG-binding-deficient Munc13-1H567K KI mice suggest that glucose-activated DAG signaling is involved in the second phase insulin response to glucose and that Munc13-1 acts as a key target of DAG/phorbol-ester. It is interesting that the effect of PMA is completely abolished in the Munc13-1 KI mice, which seems to suggest that PKC activation by PMA plays no role in the control of exocytosis in mouseβcells. However, an alternative explanation could be that PKC acts upstream of Munc13-1. The conclusive role of PKC in insulin secretion will have to wait for further detailed studies through combined efforts from genetic manipulation to integrated physiological analysis.
1) Munc13-1基因敲除小鼠出生后几个小时内死亡,我们发现培养2-3天的新生小鼠β细胞表现典型的成年小鼠β细胞特点,如Na+通道失活及对葡萄糖的响应等。本培养方法的成熟为以出生致死型基因敲除小鼠为模型研究胰岛素分泌的分子机制奠定了基础。
2)虽然Munc13-1在神经递质的释放过程中是不可缺少的因子,但它在内分泌大致密核心囊泡(LDCV)分泌的作用却尚不清楚。我们以膜电容检测和光解释钙技术相结合,发现在Munc13-1 KO小鼠中,延迟型组分的分泌几乎完全被抑制,KI小鼠中也明显降低。但是代表可释放囊泡分泌的簇发型分泌相却没有明显改变。连续去极化实验得到类似的结果,RRP排空后的恢复时间常数在KO小鼠中也明显延长。表明Munc13-1是胰岛素延迟相分泌所必需的,直接证明Munc13-1对长时程刺激下LDCV的补充起作用。由于Munc13-1的缺失使神经突触不能形成RRP囊泡,而在β细胞中却是正常的,说明Munc13-1在神经突触囊泡和LDCV的分泌中起着不同的作用。
3)胰岛素双相分泌的产生机理尚有待阐明,我们以ELISA检测Munc13-1基因敲除小鼠胰岛素分泌,发现Munc13-1缺失选择性抑制葡萄糖诱导的第二相分泌,直接证明了LDCV的成熟过程是第二相胰岛素分泌的限速步骤。
4)第二相分泌的产生或增强,需要代谢信号,而非膜去极化信号(通过KATP通道的关闭产生)的参与,然而具体参与的有哪些代谢信号还有待研究。我们对DAG接合能力缺失的Munc13-1H567K KI小鼠的研究表明葡萄糖诱导的DAG信号通路参与了胰岛素分泌的调控,Munc13-1是DAG/佛波醇通路一个关键的靶标分子。PMA能易化小鼠胰岛素的分泌,但KI小鼠中没有此效应,表明PKC不参与小鼠胰岛素分泌的调控,或作用于Munc13-1的上游。
Insulin release from pancreaticβcells in response to glucose is characterized by a biphasic time course. A full biphasic insulin response is the ultimate indication of a well-coupled healthyβcell. Interestingly, diabetes is associated with disturbance in the biphasic pattern of insulin secretion, resulting in a diminished first phase and a blunted second phase. Although first described almost 40 years ago, the cell biology of the two phase of insulin secretion remains debated. Thus it is of great importance to understand the mechanisms whereby the biphasic insulin response is generated and regulated. However, as the generation of biphasic insulin release probably involves concerted action of multi-factors, the significance of different functional LDCVs in the contribution of biphasic insulin release under glucose stimulation remains to be clarified. Munc13 proteins constitute a family of 4 mammalian homologues of C. elegans Unc-13 and Drosophila Dunc-13. Genetic deletion of Munc13-1/unc13 causes total arrest of synaptic transmission due to a complete loss of fusion-competent synaptic vesicles. Munc13 proteins contain C2 domain and a DAG binding C1 domain. The binding of DAG/phorbol-ester to C1 domain leads to enhanced priming activity of Munc13-1. The requirement of Munc13s for LDCVs, however, has not been established.
In the current study, we have aimed at elucidating the role of Munc13-1 in the insulin secretion and dissecting its site of action using Munc13-1 knockout and Munc13-1H567K knockin mice. Secretion was analyzed by a combination of capacitance and dynamic insulin release measurements. Main results of the study are as fellows.
1.Munc13-1-defecient mice die within a few hours of birth. Hence, we had to isolateβcells from newborn mice. we found isolatedβcells from newborn mice apparently developed typicalβcell characteristics including Na+ channel inactivation and response to glucose after 3 days in culture. The establishment of the experimental system will open possibility for elucidating the molecular mechanism of insulin secretion control using various knockout mice that are lethal at birth.
2. Although Munc13-1 is absolutely necessary for neurotransmitter release from synaptic vesicles, the requirement of Munc13-1 for large dense core vesicles (LDCVs) has not been demonstrated. Cm measurements combined with flash photolysis was employed to assess the exocytosis from different pools of LDCVs. We found that the sustained component of exocytosis was almost completely abolished in Munc13-1-deficientβcells, and to a lesser extent in KI cells. The exocytotic burst, which represents the releasable vesicles, was not significantly influenced. We thus conclude that Munc13-1 is required for the second phase of insulin secretion in response to glucose stimulation. This is the first evidence that Munc13-1 is required for the supply of LDCVs during prolonged stimulus. Whereas knockout of Munc13-1 causes complete loss of readily releasable synaptic vesicles, we found that readily releasable LDCVs are normal in Munc13-1-deficient beta cells. These results suggest different requirement of Munc13-1 for synaptic vesicles and LDCVs.
3. The mechanism underlying the generation of biphasic insulin response is elusive. The ultimate answer to this question would have to wait for the identification of molecular players that are specifically involved in the production of the biphasic insulin release. We now show that genetic ablation of Munc13-1 preferentially abolishes the second phase of insulin response to glucose, providing direct evidence that the priming of LDCVs from an unprimed pool constitutes the rate limiting step in the second phase of insulin release.
4. It has been demonstrated that metabolic signals, other than the membrane-depolarizing signal (generated by closing KATP channels), are required for the production (or amplification) of the second phase. However the identities of these signals remain to be identified. Our results showing that the sustained insulin release is impaired in DAG-binding-deficient Munc13-1H567K KI mice suggest that glucose-activated DAG signaling is involved in the second phase insulin response to glucose and that Munc13-1 acts as a key target of DAG/phorbol-ester. It is interesting that the effect of PMA is completely abolished in the Munc13-1 KI mice, which seems to suggest that PKC activation by PMA plays no role in the control of exocytosis in mouseβcells. However, an alternative explanation could be that PKC acts upstream of Munc13-1. The conclusive role of PKC in insulin secretion will have to wait for further detailed studies through combined efforts from genetic manipulation to integrated physiological analysis.
引文
[1] Banting, F. G. and Best, C. H. Pancreatic extracts. 1922. J Lab Clin Med, 1990, 115(2):254-272
[2] Pearse, A. G. and Polak, J. M. Neural crest origin of the endocrine polypeptide (APUD) cells of the gastrointestinal tract and pancreas. Gut, 1971, 12(10):783-788
[3] Ashcroft, F. M. and Rorsman, P. Electrophysiology of the pancreatic beta-cell. Prog Biophys Mol Biol, 1989, 54(2):87-143
[4] Boschero, A. C., Tombaccini, D. and Atwater, I. Effects of glucose on insulin release and 86Rb permeability in cultured neonatal and adult rat islets. FEBS Lett, 1988, 236(2):375-379
[5] Rorsman, P., Eliasson, L., Renstrom, E., et al. The Cell Physiology of Biphasic Insulin Secretion. News Physiol Sci, 2000, 15(72-77)
[6] Kennedy, H. J., Pouli, A. E., Ainscow, E. K., et al. Glucose generates sub-plasma membrane ATP microdomains in single islet beta-cells. Potential role for strategically located mitochondria. J Biol Chem, 1999, 274(19):13281-13291
[7] Gribble, F. M. and Reimann, F. Pharmacological modulation of K(ATP) channels. Biochem Soc Trans, 2002, 30(2):333-339
[8] Zawalich, W. S., Bonnet-Eymard, M. and Zawalich, K. C. Signal transduction in pancreatic beta-cells: regulation of insulin secretion by information flow in the phospholipase C/protein kinase C pathway. Front Biosci, 1997, 2(d160-172)
[9] Zawalich, W. S. and Zawalich, K. C. Species differences in the induction of time-dependent potentiation of insulin secretion. Endocrinology, 1996, 137(5):1664-1669
[10] Zawalich, W. S. and Zawalich, K. C. Effects of protein kinase C inhibitors on insulin secretory responses from rodent pancreatic islets. Mol Cell Endocrinol, 2001, 177(1-2):95-105
[11] Nesher, R., Anteby, E., Yedovizky, M., et al. Beta-cell protein kinases and the dynamics of the insulin response to glucose. Diabetes, 2002, 51 Suppl 1(S68-73)
[12] Cotes, P. M., Mussett, M. V., Berryman, I., et al. Collaborative study of estimates by radioimmunoassay of insulin concentrations in plasma samples examined in groups of five or six laboratories. J Endocrinol, 1969, 45(4):557-569
[13] Huang, L., Shen, H., Atkinson, M. A., et al. Detection of exocytosis at individual pancreatic beta cells by amperometry at a chemically modified microelectrode. Proc Natl Acad Sci U S A, 1995, 92(21):9608-9612
[14] Lehr, S., Herbst, M., Kampermann, J., et al. Adrenaline inhibits depolarization-induced increases in capacitance the presence of elevated [Ca2+]i in insulin secreting cells. FEBS Lett, 1997, 415(1):1-5
[15] Rorsman, P. The pancreatic beta-cell as a fuel sensor: an electrophysiologist's viewpoint. Diabetologia, 1997, 40(5):487-495
[16] Coore, H. G. and Randle, P. J. Inhibition of glucose phosphorylation by mannoheptulose. Biochem J, 1964, 91(1):56-59
[17] Gembal, M., Gilon, P. and Henquin, J. C. Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells. J Clin Invest, 1992, 89(4):1288-1295
[18] Straub, S. G., Cosgrove, K. E., Ammala, C., et al. Hyperinsulinism of infancy: the regulated release of insulin by KATP channel-independent pathways. Diabetes, 2001, 50(2):329-339
[19] Seghers, V., Nakazaki, M., DeMayo, F., et al. Sur1 knockout mice. A model for K(ATP) channel-independent regulation of insulin secretion. J Biol Chem, 2000, 275(13):9270-9277
[20] Regazzi, R., Sasaki, T., Takahashi, K., et al. Prenylcysteine analogs mimicking the C-terminus of GTP-binding proteins stimulate exocytosis from permeabilized HIT-T15 cells: comparison with the effect of Rab3AL peptide. Biochim Biophys Acta, 1995, 1268(3):269-278
[21] Parsons, T. D., Coorssen, J. R., Horstmann, H., et al. Docked granules, the exocytic burst, and the need for ATP hydrolysis in endocrine cells. Neuron, 1995, 15(5):1085-1096
[22] Takahashi, N., Kadowaki, T., Yazaki, Y., et al. Post-priming actions of ATP on Ca2+-dependent exocytosis in pancreatic beta cells. Proc Natl Acad Sci U S A, 1999, 96(2):760-765
[23] Prentki, M., Vischer, S., Glennon, M. C., et al. Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem, 1992, 267(9):5802-5810
[24] Panten, U. and Klein, H. O2 consumption by isolated pancreatic islets, as measured in a microincubation system with a Clark-type electrode. Endocrinology, 1982, 111(5):1595-1600
[25] Farfari, S., Schulz, V., Corkey, B., et al. Glucose-regulated anaplerosis and cataplerosis in pancreatic beta-cells: possible implication of a pyruvate/citrate shuttle in insulin secretion. Diabetes, 2000, 49(5):718-726
[26] Maechler, P. and Wollheim, C. B. Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature, 1999, 402(6762):685-689
[27] Aizawa, T., Komatsu, M., Asanuma, N., et al. Glucose action 'beyond ionic events' in the pancreatic beta cell. Trends Pharmacol Sci, 1998, 19(12):496-499
[28] Rutter, G. A. Insulin secretion: feed-forward control of insulin biosynthesis? Curr Biol, 1999, 9(12):R443-445
[29] Grodsky, G. M. A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling. J Clin Invest, 1972, 51(8):2047-2059
[30] Straub, S. G. and Sharp, G. W. Hypothesis: one rate-limiting step controls the magnitude of both phases of glucose-stimulated insulin secretion. Am J Physiol Cell Physiol, 2004, 287(3):C565-571
[31] Komatsu, M., Noda, M. and Sharp, G. W. Nutrient augmentation of Ca2+-dependent and Ca2+-independent pathways in stimulus-coupling to insulin secretion can be distinguished by their guanosine triphosphate requirements:studies on rat pancreatic islets. Endocrinology, 1998, 139(3):1172-1183
[32] Bratanova-Tochkova, T. K., Cheng, H., Daniel, S., et al. Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion. Diabetes, 2002, 51 Suppl 1(S83-90)
[33] Persaud, S. J., Jones, P. M. and Howell, S. L. Staurosporine inhibits protein kinases activated by Ca2+ and cyclic AMP in addition to inhibiting protein kinase C in rat islets of Langerhans. Mol Cell Endocrinol, 1993, 94(1):55-60
[34] Hashimoto, N., Kido, Y., Uchida, T., et al. PKClambda regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic beta cells. J Clin Invest, 2005, 115(1):138-145
[35] Gross, M. [Diabetes--definition and classification]. Osterr Krankenpflegez, 1996, 49(5):22-24
[36] Barker, D. J., Hales, C. N., Fall, C. H., et al. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia, 1993, 36(1):62-67
[37] Alberti, K. G. and Zimmet, P. Z. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med, 1998, 15(7):539-553
[38] Song, Y., Niu, T., Manson, J. E., et al. Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies. Am J Hum Genet, 2004, 74(2):208-222
[39] Mohlke, K. L. and Boehnke, M. The role of HNF4A variants in the risk of type 2 diabetes. Curr Diab Rep, 2005, 5(2):149-156
[40] Baroni, M. G., Oelbaum, R. S., Pozzilli, P., et al. Polymorphisms at the GLUT1 (HepG2) and GLUT4 (muscle/adipocyte) glucose transporter genes and non-insulin-dependent diabetes mellitus (NIDDM). Hum Genet, 1992, 88(5):557-561
[41] Terauchi, Y. and Kadowaki, T. Insights into molecular pathogenesis oftype 2 diabetes from knockout mouse models. Endocr J, 2002, 49(3):247-263
[42] Bray, G. A. Obesity--a disease of nutrient or energy balance? Nutr Rev, 1987, 45(2):33-43
[43] Bray, G. A. Overweight is risking fate. Definition, classification, prevalence, and risks. Ann N Y Acad Sci, 1987, 499(14-28)
[44] Bray, G. A. Obesity and reproduction. Hum Reprod, 1997, 12 Suppl 1(26-32)
[45] Lawton, C. Diabetes and aging: a growing concern. Perspectives, 1994, 18(1):7-9
[46] Segar, L. F. Diabetes and aging. J Mich State Med Soc, 1959, 58(1442-1444)
[47] Kasai, H. Comparative biology of Ca2+-dependent exocytosis: implications of kinetic diversity for secretory function. Trends Neurosci, 1999, 22(2):88-93
[48] Polasek, J. Platelet secretory granules or secretory lysosomes? Platelets, 2005, 16(8):500-501
[49] Liu, D., Xu, L., Yang, F., et al. Rapid biogenesis and sensitization of secretory lysosomes in NK cells mediated by target-cell recognition. Proc Natl Acad Sci U S A, 2005, 102(1):123-127
[50] Bossi, G. and Griffiths, G. M. CTL secretory lysosomes: biogenesis and secretion of a harmful organelle. Semin Immunol, 2005, 17(1):87-94
[51] Chieregatti, E. and Meldolesi, J. Regulated exocytosis: new organelles for non-secretory purposes. Nat Rev Mol Cell Biol, 2005, 6(2):181-187
[52] Koumanov, F., Jin, B., Yang, J., et al. Insulin signaling meets vesicle traffic of GLUT4 at a plasma-membrane-activated fusion step. Cell Metab, 2005, 2(3):179-189
[53] Elmendorf, J. S. Signals that regulate GLUT4 translocation. J Membr Biol, 2002, 190(3):167-174
[54] Furtado, L. M., Somwar, R., Sweeney, G., et al. Activation of the glucose transporter GLUT4 by insulin. Biochem Cell Biol, 2002, 80(5):569-578
[55] Sudhof, T. C. The synaptic vesicle cycle: a cascade of protein-protein interactions. Nature, 1995, 375(6533):645-653
[56] Rutter, G. A. and Tsuboi, T. Kiss and run exocytosis of dense core secretory vesicles. Neuroreport, 2004, 15(1):79-81
[57] Tsuboi, T. and Rutter, G. A. Multiple forms of "kiss-and-run" exocytosis revealed by evanescent wave microscopy. Curr Biol, 2003, 13(7):563-567
[58] Ryan, T. A. Kiss-and-run, fuse-pinch-and-linger, fuse-and-collapse: the life and times of a neurosecretory granule. Proc Natl Acad Sci U S A, 2003, 100(5):2171-2173
[59] Bennett, M. K. and Scheller, R. H. The molecular machinery for secretion is conserved from yeast to neurons. Proc Natl Acad Sci U S A, 1993, 90(7):2559-2563
[60] Jena, B. P. Molecular machinery and mechanism of cell secretion. Exp Biol Med (Maywood), 2005, 230(5):307-319
[61] Burgoyne, R. D. and Morgan, A. Secretory granule exocytosis. Physiol Rev, 2003, 83(2):581-632
[62] Mochida, S. Protein-protein interactions in neurotransmitter release. Neurosci Res, 2000, 36(3):175-182
[63] Link, E., Edelmann, L., Chou, J. H., et al. Tetanus toxin action: inhibition of neurotransmitter release linked to synaptobrevin proteolysis. Biochem Biophys Res Commun, 1992, 189(2):1017-1023
[64] Blasi, J., Chapman, E. R., Yamasaki, S., et al. Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC-1/syntaxin. Embo J, 1993, 12(12):4821-4828
[65] Schiavo, G., Poulain, B., Rossetto, O., et al. Tetanus toxin is a zinc protein and its inhibition of neurotransmitter release and protease activity depend on zinc. Embo J, 1992, 11(10):3577-3583
[66] Xu, T., Rammner, B., Margittai, M., et al. Inhibition of SNARE complex assembly differentially affects kinetic components of exocytosis. Cell, 1999,99(7):713-722
[67] Weimer, R. M., Richmond, J. E., Davis, W. S., et al. Defects in synaptic vesicle docking in unc-18 mutants. Nat Neurosci, 2003, 6(10):1023-1030
[68] Fisher, R. J., Pevsner, J. and Burgoyne, R. D. Control of fusion pore dynamics during exocytosis by Munc18. Science, 2001, 291(5505):875-878
[69] Rowe, J., Calegari, F., Taverna, E., et al. Syntaxin 1A is delivered to the apical and basolateral domains of epithelial cells: the role of munc-18 proteins. J Cell Sci, 2001, 114(Pt 18):3323-3332
[70] Toonen, R. F. and Verhage, M. Vesicle trafficking: pleasure and pain from SM genes. Trends Cell Biol, 2003, 13(4):177-186
[71] Geppert, M., Goda, Y., Stevens, C. F., et al. The small GTP-binding protein Rab3A regulates a late step in synaptic vesicle fusion. Nature, 1997, 387(6635):810-814
[72] Wang, Y., Okamoto, M., Schmitz, F., et al. Rim is a putative Rab3 effector in regulating synaptic-vesicle fusion. Nature, 1997, 388(6642):593-598
[73] Fukuda, M. Distinct Rab binding specificity of Rim1, Rim2, rabphilin, and Noc2. Identification of a critical determinant of Rab3A/Rab27A recognition by Rim2. J Biol Chem, 2003, 278(17):15373-15380
[74] Schwarz, T. L. Synaptotagmin promotes both vesicle fusion and recycling. Proc Natl Acad Sci U S A, 2004, 101(47):16401-16402
[75] Hui, E., Bai, J., Wang, P., et al. Three distinct kinetic groupings of the synaptotagmin family: candidate sensors for rapid and delayed exocytosis. Proc Natl Acad Sci U S A, 2005, 102(14):5210-5214
[76] Wan, Q. F., Dong, Y., Yang, H., et al. Protein kinase activation increases insulin secretion by sensitizing the secretory machinery to Ca2+. J Gen Physiol, 2004, 124(6):653-662
[77] Yang, Y. and Gillis, K. D. A highly Ca2+-sensitive pool of granules is regulated by glucose and protein kinases in insulin-secreting INS-1 cells. J Gen Physiol, 2004, 124(6):641-651
[78] Liu, H. S., Hu, Z. T., Zhou, K. M., et al. Heterogeneity of the Ca(2+) sensitivity of secretion in a pituitary gonadotrope cell line and its modulation by protein kinase C and Ca(2+). J Cell Physiol, 2006, 207(3):668-674
[79] Elmqvist, D. and Quastel, D. M. A quantitative study of end-plate potentials in isolated human muscle. J Physiol, 1965, 178(3):505-529
[80] Bittner, M. A. and Holz, R. W. Kinetic analysis of secretion from permeabilized adrenal chromaffin cells reveals distinct components. J Biol Chem, 1992, 267(23):16219-16225
[81] Neher, E. and Zucker, R. S. Multiple calcium-dependent processes related to secretion in bovine chromaffin cells. Neuron, 1993, 10(1):21-30
[82] Rorsman, P. and Renstrom, E. Insulin granule dynamics in pancreatic beta cells. Diabetologia, 2003, 46(8):1029-1045
[83] Barg, S., Eliasson, L., Renstrom, E., et al. A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells. Diabetes, 2002, 51 Suppl 1(S74-82)
[84] Peinado, J. R., Castano, J. P., Vazquez-Martinez, R., et al. Amphibian melanotrophs as a model to analyze the secretory plasticity of endocrine cells. Gen Comp Endocrinol, 2002, 126(1):4-6
[85] Rettig, J. and Neher, E. Emerging roles of presynaptic proteins in Ca++-triggered exocytosis. Science, 2002, 298(5594):781-785
[86] Sorensen, J. B. Formation, stabilisation and fusion of the readily releasable pool of secretory vesicles. Pflugers Arch, 2004, 448(4):347-362
[87] Lou, X., Scheuss, V. and Schneggenburger, R. Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion. Nature, 2005, 435(7041):497-501
[88] Yang, H., Liu, H., Hu, Z., et al. PKC-induced sensitization of Ca2+-dependent exocytosis is mediated by reducing the Ca2+ cooperativity in pituitary gonadotropes. J Gen Physiol, 2005, 125(3):327-334
[89] Chapman, E. R. Synaptotagmin: a Ca(2+) sensor that triggers exocytosis? Nat Rev Mol Cell Biol, 2002, 3(7):498-508
[90] Brose, N., Petrenko, A. G., Sudhof, T. C., et al. Synaptotagmin: a calcium sensor on the synaptic vesicle surface. Science, 1992, 256(5059):1021-1025
[91] Zhang, X., Rizo, J. and Sudhof, T. C. Mechanism of phospholipid binding by the C2A-domain of synaptotagmin I. Biochemistry, 1998, 37(36):12395-12403
[92] Augustine, G. J. How does calcium trigger neurotransmitter release? Curr Opin Neurobiol, 2001, 11(3):320-326
[93] O'Neill, P. J. and Rahwan, R. G. Experimental evidence for calcium independent catecholamine secretion from the bovine adrenal medulla. J Pharmacol Exp Ther, 1975, 193(2):513-522
[94] Raffaniello, R. D. and Raufman, J. P. Guanine nucleotides activate multiple signaling pathways in permeabilized gastric chief cells. Evidence for GTP gamma S-induced calcium-independent pepsinogen secretion. J Biol Chem, 1993, 268(12):8491-8496
[95] Ludowyke, R. I. and Scurr, L. L. Calcium-independent secretion by ATP gamma S from a permeabilized rat basophilic leukaemia cell line (RBL-2H3). Cell Signal, 1994, 6(2):223-231
[96] Liu, J., Wan, Q., Lin, X., et al. Alpha-latrotoxin modulates the secretory machinery via receptor-mediated activation of protein kinase C. Traffic, 2005, 6(9):756-765
[97] Bai, L., Zhu, D., Zhou, K., et al. Differential Properties of GTP- and Ca-Stimulated Exocytosis from Large Dense Core Vesicles. Traffic, 2006, 7(4):416-428
[98] Brenner, S. The genetics of Caenorhabditis elegans. Genetics, 1974, 77(1):71-94
[99] Hosono, R. and Kamiya, Y. Additional genes which result in an elevation of acetylcholine levels by mutations in Caenorhabditis elegans. Neurosci Lett, 1991, 128(2):243-244
[100] Brose, N., Hofmann, K., Hata, Y., et al. Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. J Biol Chem, 1995, 270(42):25273-25280
[101] Maruyama, I. N. and Brenner, S. A phorbol ester/diacylglycerol-binding protein encoded by the unc-13 gene of Caenorhabditis elegans. Proc Natl Acad Sci U S A, 1991, 88(13):5729-5733
[102] Richmond, J. E., Davis, W. S. and Jorgensen, E. M. UNC-13 is required for synaptic vesicle fusion in C. elegans. Nat Neurosci, 1999, 2(11):959-964
[103] Xu, X. Z., Wes, P. D., Chen, H., et al. Retinal targets for calmodulin include proteins implicated in synaptic transmission. J Biol Chem, 1998, 273(47):31297-31307
[104] Aravamudan, B., Fergestad, T., Davis, W. S., et al. Drosophila UNC-13 is essential for synaptic transmission. Nat Neurosci, 1999, 2(11):965-971
[105] Ashery, U., Varoqueaux, F., Voets, T., et al. Munc13-1 acts as a priming factor for large dense-core vesicles in bovine chromaffin cells. Embo J, 2000, 19(14):3586-3596
[106] Betz, A., Ashery, U., Rickmann, M., et al. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron, 1998, 21(1):123-136
[107] Junge, H. J., Rhee, J. S., Jahn, O., et al. Calmodulin and Munc13 form a Ca2+ sensor/effector complex that controls short-term synaptic plasticity. Cell, 2004, 118(3):389-401
[108] Augustin, I., Rosenmund, C., Sudhof, T. C., et al. Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature, 1999, 400(6743):457-461
[109] Ostenson, C. G., Gaisano, H., Sheu, L., et al. Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients. Diabetes, 2006, 55(2):435-440
[110] Sheu, L., Pasyk, E. A., Ji, J., et al. Regulation of insulin exocytosis by Munc13-1. J Biol Chem, 2003, 278(30):27556-27563
[111] Rosenmund, C., Sigler, A., Augustin, I., et al. Differential control of vesicle priming and short-term plasticity by Munc13 isoforms. Neuron, 2002,33(3):411-424
[112] Augustin, I., Korte, S., Rickmann, M., et al. The cerebellum-specific Munc13 isoform Munc13-3 regulates cerebellar synaptic transmission and motor learning in mice. J Neurosci, 2001, 21(1):10-17
[113] Betz, A., Okamoto, M., Benseler, F., et al. Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin. J Biol Chem, 1997, 272(4):2520-2526
[114] Neeb, A., Koch, H., Schurmann, A., et al. Direct interaction between the ARF-specific guanine nucleotide exchange factor msec7-1 and presynaptic Munc13-1. Eur J Cell Biol, 1999, 78(8):533-538
[115] Sassa, T., Harada, S., Ogawa, H., et al. Regulation of the UNC-18-Caenorhabditis elegans syntaxin complex by UNC-13. J Neurosci, 1999, 19(12):4772-4777
[116] Betz, A., Thakur, P., Junge, H. J., et al. Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron, 2001, 30(1):183-196
[117] Toonen, R. F., de Vries, K. J., Zalm, R., et al. Munc18-1 stabilizes syntaxin 1, but is not essential for syntaxin 1 targeting and SNARE complex formation. J Neurochem, 2005, 93(6):1393-1400
[118] Dulubova, I., Sugita, S., Hill, S., et al. A conformational switch in syntaxin during exocytosis: role of munc18. Embo J, 1999, 18(16):4372-4382
[119] Misura, K. M., Scheller, R. H. and Weis, W. I. Three-dimensional structure of the neuronal-Sec1-syntaxin 1a complex. Nature, 2000, 404(6776):355-362
[120] Verhage, M., Maia, A. S., Plomp, J. J., et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science, 2000, 287(5454):864-869
[121] Carr, C. M., Grote, E., Munson, M., et al. Sec1p binds to SNARE complexes and concentrates at sites of secretion. J Cell Biol, 1999, 146(2):333-344
[122] Rizo, J. and Sudhof, T. C. Snares and Munc18 in synaptic vesicle fusion.Nat Rev Neurosci, 2002, 3(8):641-653
[123] Richmond, J. E., Weimer, R. M. and Jorgensen, E. M. An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming. Nature, 2001, 412(6844):338-341
[124] Koushika, S. P., Richmond, J. E., Hadwiger, G., et al. A post-docking role for active zone protein Rim. Nat Neurosci, 2001, 4(10):997-1005
[125] Dulubova, I., Lou, X., Lu, J., et al. A Munc13/RIM/Rab3 tripartite complex: from priming to plasticity? Embo J, 2005, 24(16):2839-2850
[126] Neher, E. and Sakmann, B. Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature, 1976, 260(5554):799-802
[127] Gentet, L. J., Stuart, G. J. and Clements, J. D. Direct measurement of specific membrane capacitance in neurons. Biophys J, 2000, 79(1):314-320
[128] Lollike, K. and Lindau, M. Membrane capacitance techniques to monitor granule exocytosis in neutrophils. J Immunol Methods, 1999, 232(1-2):111-120
[129] Le, Y. and Sauer, B. Conditional gene knockout using cre recombinase. Methods Mol Biol, 2000, 136(477-485)
[130] Sauer, B. and Henderson, N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc Natl Acad Sci U S A, 1988, 85(14):5166-5170
[131] Sternberg, N. and Hamilton, D. Bacteriophage P1 site-specific recombination. I. Recombination between loxP sites. J Mol Biol, 1981, 150(4):467-486
[132] Rhee, J. S., Betz, A., Pyott, S., et al. Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs. Cell, 2002, 108(1):121-133
[133] Meneghel-Rozzo, T., Rozzo, A., Poppi, L., et al. In vivo and in vitro development of mouse pancreatic beta-cells in organotypic slices. Cell Tissue Res, 2004, 316(3):295-303
[134] Hole, R. L., Pian-Smith, M. C. and Sharp, G. W. Development of thebiphasic response to glucose in fetal and neonatal rat pancreas. Am J Physiol, 1988, 254(2 Pt 1):E167-174
[135] Mendonca, A. C., Carneiro, E. M., Bosqueiro, J. R., et al. Development of the insulin secretion mechanism in fetal and neonatal rat pancreatic B-cells: response to glucose, K+, theophylline, and carbamylcholine. Braz J Med Biol Res, 1998, 31(6):841-846
[136] Lee, J. W. and Romsos, D. R. Leptin-deficient mice commence hypersecreting insulin in response to acetylcholine between 1 and 2 weeks of age. Exp Biol Med (Maywood), 2001, 226(10):906-911
[137] Bergsten, P., Aoyagi, K., Persson, E., et al. Appearance of glucose-induced insulin release in fetal rat beta-cells. J Endocrinol, 1998, 158(1):115-120
[138] Weinhaus, A. J., Poronnik, P., Cook, D. I., et al. Insulin secretagogues, but not glucose, stimulate an increase in [Ca2+]i in the fetal rat beta-cell. Diabetes, 1995, 44(1):118-124
[139] Iversen, J. and Miles, D. W. Evidence for a feedback inhibition of insulin on insulin secretion in the isolated, perfused canine pancreas. Diabetes, 1971, 20(1):1-9
[140] Ammon, H. P., Reiber, C. and Verspohl, E. J. Indirect evidence for short-loop negative feedback of insulin secretion in the rat. J Endocrinol, 1991, 128(1):27-34
[141] Easom, R. A., Filler, N. R., Ings, E. M., et al. Correlation of the activation of Ca2+/calmodulin-dependent protein kinase II with the initiation of insulin secretion from perifused pancreatic islets. Endocrinology, 1997, 138(6):2359-2364
[142] Arkhammar, P., Juntti-Berggren, L., Larsson, O., et al. Protein kinase C modulates the insulin secretory process by maintaining a proper function of the beta-cell voltage-activated Ca2+ channels. J Biol Chem, 1994, 269(4):2743-2749
[143] Lou, X. L., Yu, X., Chen, X. K., et al. Na+ channel inactivation: a comparative study between pancreatic islet beta-cells and adrenal chromaffin cells in rat. J Physiol, 2003, 548(Pt 1):191-202
[144] Yang, Y., Udayasankar, S., Dunning, J., et al. A highly Ca2+-sensitive pool of vesicles is regulated by protein kinase C in adrenal chromaffin cells. Proc Natl Acad Sci U S A, 2002, 99(26):17060-17065
[145] Engisch, K. L. and Nowycky, M. C. Compensatory and excess retrieval: two types of endocytosis following single step depolarizations in bovine adrenal chromaffin cells. J Physiol, 1998, 506 ( Pt 3)(591-608)
[146] Heinemann, C., Chow, R. H., Neher, E., et al. Kinetics of the secretory response in bovine chromaffin cells following flash photolysis of caged Ca2+. Biophys J, 1994, 67(6):2546-2557
[147] Smith, C. and Neher, E. Multiple forms of endocytosis in bovine adrenal chromaffin cells. J Cell Biol, 1997, 139(4):885-894
[148] Lee, A. K. and Tse, A. Endocytosis in identified rat corticotrophs. J Physiol, 2001, 533(Pt 2):389-405
[149] Neves, G. and Lagnado, L. The kinetics of exocytosis and endocytosis in the synaptic terminal of goldfish retinal bipolar cells. J Physiol, 1999, 515 ( Pt 1)(181-202)
[150] Mansvelder, H. D. and Kits, K. S. The relation of exocytosis and rapid endocytosis to calcium entry evoked by short repetitive depolarizing pulses in rat melanotropic cells. J Neurosci, 1998, 18(1):81-92
[151] Artalejo, C. R., Elhamdani, A. and Palfrey, H. C. Sustained stimulation shifts the mechanism of endocytosis from dynamin-1-dependent rapid endocytosis to clathrin- and dynamin-2-mediated slow endocytosis in chromaffin cells. Proc Natl Acad Sci U S A, 2002, 99(9):6358-6363
[152] Curry, D. L., Bennett, L. L. and Grodsky, G. M. Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology, 1968, 83(3):572-584
[153] Straub, S. G. and Sharp, G. W. Glucose-stimulated signaling pathways in biphasic insulin secretion. Diabetes Metab Res Rev, 2002, 18(6):451-463
[154] Olofsson, C. S., Gopel, S. O., Barg, S., et al. Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells. Pflugers Arch, 2002, 444(1-2):43-51
[155] Koch, H., Hofmann, K. and Brose, N. Definition of Munc13-homology-domains and characterization of a novel ubiquitously expressed Munc13 isoform. Biochem J, 2000, 349(Pt 1):247-253
[156] Stevens, D. R., Wu, Z. X., Matti, U., et al. Identification of the minimal protein domain required for priming activity of Munc13-1. Curr Biol, 2005, 15(24):2243-2248
[157] Neher, E. Vesicle pools and Ca2+ microdomains: new tools for understanding their roles in neurotransmitter release. Neuron, 1998, 20(3):389-399
[158] Braun, M., Wendt, A., Birnir, B., et al. Regulated exocytosis of GABA-containing synaptic-like microvesicles in pancreatic beta-cells. J Gen Physiol, 2004, 123(3):191-204
[159] Xu, T., Binz, T., Niemann, H., et al. Multiple kinetic components of exocytosis distinguished by neurotoxin sensitivity. Nat Neurosci, 1998, 1(3):192-200
[160] Takahashi, N., Kadowaki, T., Yazaki, Y., et al. Multiple exocytotic pathways in pancreatic beta cells. J Cell Biol, 1997, 138(1):55-64
[161] Kanno, T., Ma, X., Barg, S., et al. Large dense-core vesicle exocytosis in pancreatic beta-cells monitored by capacitance measurements. Methods, 2004, 33(4):302-311
[162] Jing, X., Li, D. Q., Olofsson, C. S., et al. CaV2.3 calcium channels control second-phase insulin release. J Clin Invest, 2005, 115(1):146-154
[163] Berggren, P. O., Yang, S. N., Murakami, M., et al. Removal of Ca2+ channel beta3 subunit enhances Ca2+ oscillation frequency and insulin exocytosis. Cell, 2004, 119(2):273-284
[2] Pearse, A. G. and Polak, J. M. Neural crest origin of the endocrine polypeptide (APUD) cells of the gastrointestinal tract and pancreas. Gut, 1971, 12(10):783-788
[3] Ashcroft, F. M. and Rorsman, P. Electrophysiology of the pancreatic beta-cell. Prog Biophys Mol Biol, 1989, 54(2):87-143
[4] Boschero, A. C., Tombaccini, D. and Atwater, I. Effects of glucose on insulin release and 86Rb permeability in cultured neonatal and adult rat islets. FEBS Lett, 1988, 236(2):375-379
[5] Rorsman, P., Eliasson, L., Renstrom, E., et al. The Cell Physiology of Biphasic Insulin Secretion. News Physiol Sci, 2000, 15(72-77)
[6] Kennedy, H. J., Pouli, A. E., Ainscow, E. K., et al. Glucose generates sub-plasma membrane ATP microdomains in single islet beta-cells. Potential role for strategically located mitochondria. J Biol Chem, 1999, 274(19):13281-13291
[7] Gribble, F. M. and Reimann, F. Pharmacological modulation of K(ATP) channels. Biochem Soc Trans, 2002, 30(2):333-339
[8] Zawalich, W. S., Bonnet-Eymard, M. and Zawalich, K. C. Signal transduction in pancreatic beta-cells: regulation of insulin secretion by information flow in the phospholipase C/protein kinase C pathway. Front Biosci, 1997, 2(d160-172)
[9] Zawalich, W. S. and Zawalich, K. C. Species differences in the induction of time-dependent potentiation of insulin secretion. Endocrinology, 1996, 137(5):1664-1669
[10] Zawalich, W. S. and Zawalich, K. C. Effects of protein kinase C inhibitors on insulin secretory responses from rodent pancreatic islets. Mol Cell Endocrinol, 2001, 177(1-2):95-105
[11] Nesher, R., Anteby, E., Yedovizky, M., et al. Beta-cell protein kinases and the dynamics of the insulin response to glucose. Diabetes, 2002, 51 Suppl 1(S68-73)
[12] Cotes, P. M., Mussett, M. V., Berryman, I., et al. Collaborative study of estimates by radioimmunoassay of insulin concentrations in plasma samples examined in groups of five or six laboratories. J Endocrinol, 1969, 45(4):557-569
[13] Huang, L., Shen, H., Atkinson, M. A., et al. Detection of exocytosis at individual pancreatic beta cells by amperometry at a chemically modified microelectrode. Proc Natl Acad Sci U S A, 1995, 92(21):9608-9612
[14] Lehr, S., Herbst, M., Kampermann, J., et al. Adrenaline inhibits depolarization-induced increases in capacitance the presence of elevated [Ca2+]i in insulin secreting cells. FEBS Lett, 1997, 415(1):1-5
[15] Rorsman, P. The pancreatic beta-cell as a fuel sensor: an electrophysiologist's viewpoint. Diabetologia, 1997, 40(5):487-495
[16] Coore, H. G. and Randle, P. J. Inhibition of glucose phosphorylation by mannoheptulose. Biochem J, 1964, 91(1):56-59
[17] Gembal, M., Gilon, P. and Henquin, J. C. Evidence that glucose can control insulin release independently from its action on ATP-sensitive K+ channels in mouse B cells. J Clin Invest, 1992, 89(4):1288-1295
[18] Straub, S. G., Cosgrove, K. E., Ammala, C., et al. Hyperinsulinism of infancy: the regulated release of insulin by KATP channel-independent pathways. Diabetes, 2001, 50(2):329-339
[19] Seghers, V., Nakazaki, M., DeMayo, F., et al. Sur1 knockout mice. A model for K(ATP) channel-independent regulation of insulin secretion. J Biol Chem, 2000, 275(13):9270-9277
[20] Regazzi, R., Sasaki, T., Takahashi, K., et al. Prenylcysteine analogs mimicking the C-terminus of GTP-binding proteins stimulate exocytosis from permeabilized HIT-T15 cells: comparison with the effect of Rab3AL peptide. Biochim Biophys Acta, 1995, 1268(3):269-278
[21] Parsons, T. D., Coorssen, J. R., Horstmann, H., et al. Docked granules, the exocytic burst, and the need for ATP hydrolysis in endocrine cells. Neuron, 1995, 15(5):1085-1096
[22] Takahashi, N., Kadowaki, T., Yazaki, Y., et al. Post-priming actions of ATP on Ca2+-dependent exocytosis in pancreatic beta cells. Proc Natl Acad Sci U S A, 1999, 96(2):760-765
[23] Prentki, M., Vischer, S., Glennon, M. C., et al. Malonyl-CoA and long chain acyl-CoA esters as metabolic coupling factors in nutrient-induced insulin secretion. J Biol Chem, 1992, 267(9):5802-5810
[24] Panten, U. and Klein, H. O2 consumption by isolated pancreatic islets, as measured in a microincubation system with a Clark-type electrode. Endocrinology, 1982, 111(5):1595-1600
[25] Farfari, S., Schulz, V., Corkey, B., et al. Glucose-regulated anaplerosis and cataplerosis in pancreatic beta-cells: possible implication of a pyruvate/citrate shuttle in insulin secretion. Diabetes, 2000, 49(5):718-726
[26] Maechler, P. and Wollheim, C. B. Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature, 1999, 402(6762):685-689
[27] Aizawa, T., Komatsu, M., Asanuma, N., et al. Glucose action 'beyond ionic events' in the pancreatic beta cell. Trends Pharmacol Sci, 1998, 19(12):496-499
[28] Rutter, G. A. Insulin secretion: feed-forward control of insulin biosynthesis? Curr Biol, 1999, 9(12):R443-445
[29] Grodsky, G. M. A threshold distribution hypothesis for packet storage of insulin and its mathematical modeling. J Clin Invest, 1972, 51(8):2047-2059
[30] Straub, S. G. and Sharp, G. W. Hypothesis: one rate-limiting step controls the magnitude of both phases of glucose-stimulated insulin secretion. Am J Physiol Cell Physiol, 2004, 287(3):C565-571
[31] Komatsu, M., Noda, M. and Sharp, G. W. Nutrient augmentation of Ca2+-dependent and Ca2+-independent pathways in stimulus-coupling to insulin secretion can be distinguished by their guanosine triphosphate requirements:studies on rat pancreatic islets. Endocrinology, 1998, 139(3):1172-1183
[32] Bratanova-Tochkova, T. K., Cheng, H., Daniel, S., et al. Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion. Diabetes, 2002, 51 Suppl 1(S83-90)
[33] Persaud, S. J., Jones, P. M. and Howell, S. L. Staurosporine inhibits protein kinases activated by Ca2+ and cyclic AMP in addition to inhibiting protein kinase C in rat islets of Langerhans. Mol Cell Endocrinol, 1993, 94(1):55-60
[34] Hashimoto, N., Kido, Y., Uchida, T., et al. PKClambda regulates glucose-induced insulin secretion through modulation of gene expression in pancreatic beta cells. J Clin Invest, 2005, 115(1):138-145
[35] Gross, M. [Diabetes--definition and classification]. Osterr Krankenpflegez, 1996, 49(5):22-24
[36] Barker, D. J., Hales, C. N., Fall, C. H., et al. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia, 1993, 36(1):62-67
[37] Alberti, K. G. and Zimmet, P. Z. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med, 1998, 15(7):539-553
[38] Song, Y., Niu, T., Manson, J. E., et al. Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies. Am J Hum Genet, 2004, 74(2):208-222
[39] Mohlke, K. L. and Boehnke, M. The role of HNF4A variants in the risk of type 2 diabetes. Curr Diab Rep, 2005, 5(2):149-156
[40] Baroni, M. G., Oelbaum, R. S., Pozzilli, P., et al. Polymorphisms at the GLUT1 (HepG2) and GLUT4 (muscle/adipocyte) glucose transporter genes and non-insulin-dependent diabetes mellitus (NIDDM). Hum Genet, 1992, 88(5):557-561
[41] Terauchi, Y. and Kadowaki, T. Insights into molecular pathogenesis oftype 2 diabetes from knockout mouse models. Endocr J, 2002, 49(3):247-263
[42] Bray, G. A. Obesity--a disease of nutrient or energy balance? Nutr Rev, 1987, 45(2):33-43
[43] Bray, G. A. Overweight is risking fate. Definition, classification, prevalence, and risks. Ann N Y Acad Sci, 1987, 499(14-28)
[44] Bray, G. A. Obesity and reproduction. Hum Reprod, 1997, 12 Suppl 1(26-32)
[45] Lawton, C. Diabetes and aging: a growing concern. Perspectives, 1994, 18(1):7-9
[46] Segar, L. F. Diabetes and aging. J Mich State Med Soc, 1959, 58(1442-1444)
[47] Kasai, H. Comparative biology of Ca2+-dependent exocytosis: implications of kinetic diversity for secretory function. Trends Neurosci, 1999, 22(2):88-93
[48] Polasek, J. Platelet secretory granules or secretory lysosomes? Platelets, 2005, 16(8):500-501
[49] Liu, D., Xu, L., Yang, F., et al. Rapid biogenesis and sensitization of secretory lysosomes in NK cells mediated by target-cell recognition. Proc Natl Acad Sci U S A, 2005, 102(1):123-127
[50] Bossi, G. and Griffiths, G. M. CTL secretory lysosomes: biogenesis and secretion of a harmful organelle. Semin Immunol, 2005, 17(1):87-94
[51] Chieregatti, E. and Meldolesi, J. Regulated exocytosis: new organelles for non-secretory purposes. Nat Rev Mol Cell Biol, 2005, 6(2):181-187
[52] Koumanov, F., Jin, B., Yang, J., et al. Insulin signaling meets vesicle traffic of GLUT4 at a plasma-membrane-activated fusion step. Cell Metab, 2005, 2(3):179-189
[53] Elmendorf, J. S. Signals that regulate GLUT4 translocation. J Membr Biol, 2002, 190(3):167-174
[54] Furtado, L. M., Somwar, R., Sweeney, G., et al. Activation of the glucose transporter GLUT4 by insulin. Biochem Cell Biol, 2002, 80(5):569-578
[55] Sudhof, T. C. The synaptic vesicle cycle: a cascade of protein-protein interactions. Nature, 1995, 375(6533):645-653
[56] Rutter, G. A. and Tsuboi, T. Kiss and run exocytosis of dense core secretory vesicles. Neuroreport, 2004, 15(1):79-81
[57] Tsuboi, T. and Rutter, G. A. Multiple forms of "kiss-and-run" exocytosis revealed by evanescent wave microscopy. Curr Biol, 2003, 13(7):563-567
[58] Ryan, T. A. Kiss-and-run, fuse-pinch-and-linger, fuse-and-collapse: the life and times of a neurosecretory granule. Proc Natl Acad Sci U S A, 2003, 100(5):2171-2173
[59] Bennett, M. K. and Scheller, R. H. The molecular machinery for secretion is conserved from yeast to neurons. Proc Natl Acad Sci U S A, 1993, 90(7):2559-2563
[60] Jena, B. P. Molecular machinery and mechanism of cell secretion. Exp Biol Med (Maywood), 2005, 230(5):307-319
[61] Burgoyne, R. D. and Morgan, A. Secretory granule exocytosis. Physiol Rev, 2003, 83(2):581-632
[62] Mochida, S. Protein-protein interactions in neurotransmitter release. Neurosci Res, 2000, 36(3):175-182
[63] Link, E., Edelmann, L., Chou, J. H., et al. Tetanus toxin action: inhibition of neurotransmitter release linked to synaptobrevin proteolysis. Biochem Biophys Res Commun, 1992, 189(2):1017-1023
[64] Blasi, J., Chapman, E. R., Yamasaki, S., et al. Botulinum neurotoxin C1 blocks neurotransmitter release by means of cleaving HPC-1/syntaxin. Embo J, 1993, 12(12):4821-4828
[65] Schiavo, G., Poulain, B., Rossetto, O., et al. Tetanus toxin is a zinc protein and its inhibition of neurotransmitter release and protease activity depend on zinc. Embo J, 1992, 11(10):3577-3583
[66] Xu, T., Rammner, B., Margittai, M., et al. Inhibition of SNARE complex assembly differentially affects kinetic components of exocytosis. Cell, 1999,99(7):713-722
[67] Weimer, R. M., Richmond, J. E., Davis, W. S., et al. Defects in synaptic vesicle docking in unc-18 mutants. Nat Neurosci, 2003, 6(10):1023-1030
[68] Fisher, R. J., Pevsner, J. and Burgoyne, R. D. Control of fusion pore dynamics during exocytosis by Munc18. Science, 2001, 291(5505):875-878
[69] Rowe, J., Calegari, F., Taverna, E., et al. Syntaxin 1A is delivered to the apical and basolateral domains of epithelial cells: the role of munc-18 proteins. J Cell Sci, 2001, 114(Pt 18):3323-3332
[70] Toonen, R. F. and Verhage, M. Vesicle trafficking: pleasure and pain from SM genes. Trends Cell Biol, 2003, 13(4):177-186
[71] Geppert, M., Goda, Y., Stevens, C. F., et al. The small GTP-binding protein Rab3A regulates a late step in synaptic vesicle fusion. Nature, 1997, 387(6635):810-814
[72] Wang, Y., Okamoto, M., Schmitz, F., et al. Rim is a putative Rab3 effector in regulating synaptic-vesicle fusion. Nature, 1997, 388(6642):593-598
[73] Fukuda, M. Distinct Rab binding specificity of Rim1, Rim2, rabphilin, and Noc2. Identification of a critical determinant of Rab3A/Rab27A recognition by Rim2. J Biol Chem, 2003, 278(17):15373-15380
[74] Schwarz, T. L. Synaptotagmin promotes both vesicle fusion and recycling. Proc Natl Acad Sci U S A, 2004, 101(47):16401-16402
[75] Hui, E., Bai, J., Wang, P., et al. Three distinct kinetic groupings of the synaptotagmin family: candidate sensors for rapid and delayed exocytosis. Proc Natl Acad Sci U S A, 2005, 102(14):5210-5214
[76] Wan, Q. F., Dong, Y., Yang, H., et al. Protein kinase activation increases insulin secretion by sensitizing the secretory machinery to Ca2+. J Gen Physiol, 2004, 124(6):653-662
[77] Yang, Y. and Gillis, K. D. A highly Ca2+-sensitive pool of granules is regulated by glucose and protein kinases in insulin-secreting INS-1 cells. J Gen Physiol, 2004, 124(6):641-651
[78] Liu, H. S., Hu, Z. T., Zhou, K. M., et al. Heterogeneity of the Ca(2+) sensitivity of secretion in a pituitary gonadotrope cell line and its modulation by protein kinase C and Ca(2+). J Cell Physiol, 2006, 207(3):668-674
[79] Elmqvist, D. and Quastel, D. M. A quantitative study of end-plate potentials in isolated human muscle. J Physiol, 1965, 178(3):505-529
[80] Bittner, M. A. and Holz, R. W. Kinetic analysis of secretion from permeabilized adrenal chromaffin cells reveals distinct components. J Biol Chem, 1992, 267(23):16219-16225
[81] Neher, E. and Zucker, R. S. Multiple calcium-dependent processes related to secretion in bovine chromaffin cells. Neuron, 1993, 10(1):21-30
[82] Rorsman, P. and Renstrom, E. Insulin granule dynamics in pancreatic beta cells. Diabetologia, 2003, 46(8):1029-1045
[83] Barg, S., Eliasson, L., Renstrom, E., et al. A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells. Diabetes, 2002, 51 Suppl 1(S74-82)
[84] Peinado, J. R., Castano, J. P., Vazquez-Martinez, R., et al. Amphibian melanotrophs as a model to analyze the secretory plasticity of endocrine cells. Gen Comp Endocrinol, 2002, 126(1):4-6
[85] Rettig, J. and Neher, E. Emerging roles of presynaptic proteins in Ca++-triggered exocytosis. Science, 2002, 298(5594):781-785
[86] Sorensen, J. B. Formation, stabilisation and fusion of the readily releasable pool of secretory vesicles. Pflugers Arch, 2004, 448(4):347-362
[87] Lou, X., Scheuss, V. and Schneggenburger, R. Allosteric modulation of the presynaptic Ca2+ sensor for vesicle fusion. Nature, 2005, 435(7041):497-501
[88] Yang, H., Liu, H., Hu, Z., et al. PKC-induced sensitization of Ca2+-dependent exocytosis is mediated by reducing the Ca2+ cooperativity in pituitary gonadotropes. J Gen Physiol, 2005, 125(3):327-334
[89] Chapman, E. R. Synaptotagmin: a Ca(2+) sensor that triggers exocytosis? Nat Rev Mol Cell Biol, 2002, 3(7):498-508
[90] Brose, N., Petrenko, A. G., Sudhof, T. C., et al. Synaptotagmin: a calcium sensor on the synaptic vesicle surface. Science, 1992, 256(5059):1021-1025
[91] Zhang, X., Rizo, J. and Sudhof, T. C. Mechanism of phospholipid binding by the C2A-domain of synaptotagmin I. Biochemistry, 1998, 37(36):12395-12403
[92] Augustine, G. J. How does calcium trigger neurotransmitter release? Curr Opin Neurobiol, 2001, 11(3):320-326
[93] O'Neill, P. J. and Rahwan, R. G. Experimental evidence for calcium independent catecholamine secretion from the bovine adrenal medulla. J Pharmacol Exp Ther, 1975, 193(2):513-522
[94] Raffaniello, R. D. and Raufman, J. P. Guanine nucleotides activate multiple signaling pathways in permeabilized gastric chief cells. Evidence for GTP gamma S-induced calcium-independent pepsinogen secretion. J Biol Chem, 1993, 268(12):8491-8496
[95] Ludowyke, R. I. and Scurr, L. L. Calcium-independent secretion by ATP gamma S from a permeabilized rat basophilic leukaemia cell line (RBL-2H3). Cell Signal, 1994, 6(2):223-231
[96] Liu, J., Wan, Q., Lin, X., et al. Alpha-latrotoxin modulates the secretory machinery via receptor-mediated activation of protein kinase C. Traffic, 2005, 6(9):756-765
[97] Bai, L., Zhu, D., Zhou, K., et al. Differential Properties of GTP- and Ca-Stimulated Exocytosis from Large Dense Core Vesicles. Traffic, 2006, 7(4):416-428
[98] Brenner, S. The genetics of Caenorhabditis elegans. Genetics, 1974, 77(1):71-94
[99] Hosono, R. and Kamiya, Y. Additional genes which result in an elevation of acetylcholine levels by mutations in Caenorhabditis elegans. Neurosci Lett, 1991, 128(2):243-244
[100] Brose, N., Hofmann, K., Hata, Y., et al. Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. J Biol Chem, 1995, 270(42):25273-25280
[101] Maruyama, I. N. and Brenner, S. A phorbol ester/diacylglycerol-binding protein encoded by the unc-13 gene of Caenorhabditis elegans. Proc Natl Acad Sci U S A, 1991, 88(13):5729-5733
[102] Richmond, J. E., Davis, W. S. and Jorgensen, E. M. UNC-13 is required for synaptic vesicle fusion in C. elegans. Nat Neurosci, 1999, 2(11):959-964
[103] Xu, X. Z., Wes, P. D., Chen, H., et al. Retinal targets for calmodulin include proteins implicated in synaptic transmission. J Biol Chem, 1998, 273(47):31297-31307
[104] Aravamudan, B., Fergestad, T., Davis, W. S., et al. Drosophila UNC-13 is essential for synaptic transmission. Nat Neurosci, 1999, 2(11):965-971
[105] Ashery, U., Varoqueaux, F., Voets, T., et al. Munc13-1 acts as a priming factor for large dense-core vesicles in bovine chromaffin cells. Embo J, 2000, 19(14):3586-3596
[106] Betz, A., Ashery, U., Rickmann, M., et al. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron, 1998, 21(1):123-136
[107] Junge, H. J., Rhee, J. S., Jahn, O., et al. Calmodulin and Munc13 form a Ca2+ sensor/effector complex that controls short-term synaptic plasticity. Cell, 2004, 118(3):389-401
[108] Augustin, I., Rosenmund, C., Sudhof, T. C., et al. Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature, 1999, 400(6743):457-461
[109] Ostenson, C. G., Gaisano, H., Sheu, L., et al. Impaired gene and protein expression of exocytotic soluble N-ethylmaleimide attachment protein receptor complex proteins in pancreatic islets of type 2 diabetic patients. Diabetes, 2006, 55(2):435-440
[110] Sheu, L., Pasyk, E. A., Ji, J., et al. Regulation of insulin exocytosis by Munc13-1. J Biol Chem, 2003, 278(30):27556-27563
[111] Rosenmund, C., Sigler, A., Augustin, I., et al. Differential control of vesicle priming and short-term plasticity by Munc13 isoforms. Neuron, 2002,33(3):411-424
[112] Augustin, I., Korte, S., Rickmann, M., et al. The cerebellum-specific Munc13 isoform Munc13-3 regulates cerebellar synaptic transmission and motor learning in mice. J Neurosci, 2001, 21(1):10-17
[113] Betz, A., Okamoto, M., Benseler, F., et al. Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin. J Biol Chem, 1997, 272(4):2520-2526
[114] Neeb, A., Koch, H., Schurmann, A., et al. Direct interaction between the ARF-specific guanine nucleotide exchange factor msec7-1 and presynaptic Munc13-1. Eur J Cell Biol, 1999, 78(8):533-538
[115] Sassa, T., Harada, S., Ogawa, H., et al. Regulation of the UNC-18-Caenorhabditis elegans syntaxin complex by UNC-13. J Neurosci, 1999, 19(12):4772-4777
[116] Betz, A., Thakur, P., Junge, H. J., et al. Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron, 2001, 30(1):183-196
[117] Toonen, R. F., de Vries, K. J., Zalm, R., et al. Munc18-1 stabilizes syntaxin 1, but is not essential for syntaxin 1 targeting and SNARE complex formation. J Neurochem, 2005, 93(6):1393-1400
[118] Dulubova, I., Sugita, S., Hill, S., et al. A conformational switch in syntaxin during exocytosis: role of munc18. Embo J, 1999, 18(16):4372-4382
[119] Misura, K. M., Scheller, R. H. and Weis, W. I. Three-dimensional structure of the neuronal-Sec1-syntaxin 1a complex. Nature, 2000, 404(6776):355-362
[120] Verhage, M., Maia, A. S., Plomp, J. J., et al. Synaptic assembly of the brain in the absence of neurotransmitter secretion. Science, 2000, 287(5454):864-869
[121] Carr, C. M., Grote, E., Munson, M., et al. Sec1p binds to SNARE complexes and concentrates at sites of secretion. J Cell Biol, 1999, 146(2):333-344
[122] Rizo, J. and Sudhof, T. C. Snares and Munc18 in synaptic vesicle fusion.Nat Rev Neurosci, 2002, 3(8):641-653
[123] Richmond, J. E., Weimer, R. M. and Jorgensen, E. M. An open form of syntaxin bypasses the requirement for UNC-13 in vesicle priming. Nature, 2001, 412(6844):338-341
[124] Koushika, S. P., Richmond, J. E., Hadwiger, G., et al. A post-docking role for active zone protein Rim. Nat Neurosci, 2001, 4(10):997-1005
[125] Dulubova, I., Lou, X., Lu, J., et al. A Munc13/RIM/Rab3 tripartite complex: from priming to plasticity? Embo J, 2005, 24(16):2839-2850
[126] Neher, E. and Sakmann, B. Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature, 1976, 260(5554):799-802
[127] Gentet, L. J., Stuart, G. J. and Clements, J. D. Direct measurement of specific membrane capacitance in neurons. Biophys J, 2000, 79(1):314-320
[128] Lollike, K. and Lindau, M. Membrane capacitance techniques to monitor granule exocytosis in neutrophils. J Immunol Methods, 1999, 232(1-2):111-120
[129] Le, Y. and Sauer, B. Conditional gene knockout using cre recombinase. Methods Mol Biol, 2000, 136(477-485)
[130] Sauer, B. and Henderson, N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc Natl Acad Sci U S A, 1988, 85(14):5166-5170
[131] Sternberg, N. and Hamilton, D. Bacteriophage P1 site-specific recombination. I. Recombination between loxP sites. J Mol Biol, 1981, 150(4):467-486
[132] Rhee, J. S., Betz, A., Pyott, S., et al. Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs. Cell, 2002, 108(1):121-133
[133] Meneghel-Rozzo, T., Rozzo, A., Poppi, L., et al. In vivo and in vitro development of mouse pancreatic beta-cells in organotypic slices. Cell Tissue Res, 2004, 316(3):295-303
[134] Hole, R. L., Pian-Smith, M. C. and Sharp, G. W. Development of thebiphasic response to glucose in fetal and neonatal rat pancreas. Am J Physiol, 1988, 254(2 Pt 1):E167-174
[135] Mendonca, A. C., Carneiro, E. M., Bosqueiro, J. R., et al. Development of the insulin secretion mechanism in fetal and neonatal rat pancreatic B-cells: response to glucose, K+, theophylline, and carbamylcholine. Braz J Med Biol Res, 1998, 31(6):841-846
[136] Lee, J. W. and Romsos, D. R. Leptin-deficient mice commence hypersecreting insulin in response to acetylcholine between 1 and 2 weeks of age. Exp Biol Med (Maywood), 2001, 226(10):906-911
[137] Bergsten, P., Aoyagi, K., Persson, E., et al. Appearance of glucose-induced insulin release in fetal rat beta-cells. J Endocrinol, 1998, 158(1):115-120
[138] Weinhaus, A. J., Poronnik, P., Cook, D. I., et al. Insulin secretagogues, but not glucose, stimulate an increase in [Ca2+]i in the fetal rat beta-cell. Diabetes, 1995, 44(1):118-124
[139] Iversen, J. and Miles, D. W. Evidence for a feedback inhibition of insulin on insulin secretion in the isolated, perfused canine pancreas. Diabetes, 1971, 20(1):1-9
[140] Ammon, H. P., Reiber, C. and Verspohl, E. J. Indirect evidence for short-loop negative feedback of insulin secretion in the rat. J Endocrinol, 1991, 128(1):27-34
[141] Easom, R. A., Filler, N. R., Ings, E. M., et al. Correlation of the activation of Ca2+/calmodulin-dependent protein kinase II with the initiation of insulin secretion from perifused pancreatic islets. Endocrinology, 1997, 138(6):2359-2364
[142] Arkhammar, P., Juntti-Berggren, L., Larsson, O., et al. Protein kinase C modulates the insulin secretory process by maintaining a proper function of the beta-cell voltage-activated Ca2+ channels. J Biol Chem, 1994, 269(4):2743-2749
[143] Lou, X. L., Yu, X., Chen, X. K., et al. Na+ channel inactivation: a comparative study between pancreatic islet beta-cells and adrenal chromaffin cells in rat. J Physiol, 2003, 548(Pt 1):191-202
[144] Yang, Y., Udayasankar, S., Dunning, J., et al. A highly Ca2+-sensitive pool of vesicles is regulated by protein kinase C in adrenal chromaffin cells. Proc Natl Acad Sci U S A, 2002, 99(26):17060-17065
[145] Engisch, K. L. and Nowycky, M. C. Compensatory and excess retrieval: two types of endocytosis following single step depolarizations in bovine adrenal chromaffin cells. J Physiol, 1998, 506 ( Pt 3)(591-608)
[146] Heinemann, C., Chow, R. H., Neher, E., et al. Kinetics of the secretory response in bovine chromaffin cells following flash photolysis of caged Ca2+. Biophys J, 1994, 67(6):2546-2557
[147] Smith, C. and Neher, E. Multiple forms of endocytosis in bovine adrenal chromaffin cells. J Cell Biol, 1997, 139(4):885-894
[148] Lee, A. K. and Tse, A. Endocytosis in identified rat corticotrophs. J Physiol, 2001, 533(Pt 2):389-405
[149] Neves, G. and Lagnado, L. The kinetics of exocytosis and endocytosis in the synaptic terminal of goldfish retinal bipolar cells. J Physiol, 1999, 515 ( Pt 1)(181-202)
[150] Mansvelder, H. D. and Kits, K. S. The relation of exocytosis and rapid endocytosis to calcium entry evoked by short repetitive depolarizing pulses in rat melanotropic cells. J Neurosci, 1998, 18(1):81-92
[151] Artalejo, C. R., Elhamdani, A. and Palfrey, H. C. Sustained stimulation shifts the mechanism of endocytosis from dynamin-1-dependent rapid endocytosis to clathrin- and dynamin-2-mediated slow endocytosis in chromaffin cells. Proc Natl Acad Sci U S A, 2002, 99(9):6358-6363
[152] Curry, D. L., Bennett, L. L. and Grodsky, G. M. Dynamics of insulin secretion by the perfused rat pancreas. Endocrinology, 1968, 83(3):572-584
[153] Straub, S. G. and Sharp, G. W. Glucose-stimulated signaling pathways in biphasic insulin secretion. Diabetes Metab Res Rev, 2002, 18(6):451-463
[154] Olofsson, C. S., Gopel, S. O., Barg, S., et al. Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells. Pflugers Arch, 2002, 444(1-2):43-51
[155] Koch, H., Hofmann, K. and Brose, N. Definition of Munc13-homology-domains and characterization of a novel ubiquitously expressed Munc13 isoform. Biochem J, 2000, 349(Pt 1):247-253
[156] Stevens, D. R., Wu, Z. X., Matti, U., et al. Identification of the minimal protein domain required for priming activity of Munc13-1. Curr Biol, 2005, 15(24):2243-2248
[157] Neher, E. Vesicle pools and Ca2+ microdomains: new tools for understanding their roles in neurotransmitter release. Neuron, 1998, 20(3):389-399
[158] Braun, M., Wendt, A., Birnir, B., et al. Regulated exocytosis of GABA-containing synaptic-like microvesicles in pancreatic beta-cells. J Gen Physiol, 2004, 123(3):191-204
[159] Xu, T., Binz, T., Niemann, H., et al. Multiple kinetic components of exocytosis distinguished by neurotoxin sensitivity. Nat Neurosci, 1998, 1(3):192-200
[160] Takahashi, N., Kadowaki, T., Yazaki, Y., et al. Multiple exocytotic pathways in pancreatic beta cells. J Cell Biol, 1997, 138(1):55-64
[161] Kanno, T., Ma, X., Barg, S., et al. Large dense-core vesicle exocytosis in pancreatic beta-cells monitored by capacitance measurements. Methods, 2004, 33(4):302-311
[162] Jing, X., Li, D. Q., Olofsson, C. S., et al. CaV2.3 calcium channels control second-phase insulin release. J Clin Invest, 2005, 115(1):146-154
[163] Berggren, P. O., Yang, S. N., Murakami, M., et al. Removal of Ca2+ channel beta3 subunit enhances Ca2+ oscillation frequency and insulin exocytosis. Cell, 2004, 119(2):273-284