Identification and Biochemical Characterization of a Novel Nortriterpene Inhibitor of the Human Lymphocyte Voltage-Gated Potassium Channel, Kv1.3

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• 作者：John P. Felix ; Randal M. Bugianesi ; William A. Schmalhofer ; Robert Borris ; Michael A. Goetz ; Otto D. Hensens ; Jian-Ming Bao ; Frank Kayser ; William H. Parsons ; Kathleen Rupprecht ; Maria L. Garcia ; Greg
• 刊名：Biochemistry
• 出版年：1999
• 出版时间：April 20, 1999
• 年：1999
• 卷：38
• 期：16
• 页码：4922 - 4930
• 全文大小：102K
• 年卷期：v.38,no.16(April 20, 1999)
• ISSN：1520-4995

文摘

A novel nortriterpene, termed correolide, purified from the tree Spachea correae, inhibits Kv1.3,a Shaker-type delayed rectifier potassium channel present in human T lymphocytes. Correolide inhibits⁸⁶Rb⁺ efflux through Kv1.3 channels expressed in CHO cells (IC₅₀ 86 nM; Hill coefficient 1) and displaysa defined structure-activity relationship. Potency in this assay increases with preincubation time andwith time after channel opening. Correolide displays marked selectivity against numerous receptors andvoltage- and ligand-gated ion channels. Although correolide is most potent as a Kv1.3 inhibitor, it blocksall other members of the Kv1 family with 4-14-fold lower potency. C20-29-[³H]dihydrocorreolide (diTC)was prepared and shown to bind in a specific, saturable, and reversible fashion (K_d = 11 nM) to a singleclass of sites in membranes prepared from CHO/Kv1.3 cells. The molecular pharmacology andstoichiometry of this binding reaction suggest that one diTC site is present per Kv1.3 channel tetramer.This site is allosterically coupled to peptide and potassium binding sites in the pore of the channel. DiTCbinding to human brain synaptic membranes identifies channels composed of other Kv1 family members.Correolide depolarizes human T cells to the same extent as peptidyl inhibitors of Kv1.3, suggesting thatit is a candidate for development as an immunosuppressant. Correolide is the first potent, small moleculeinhibitor of Kv1 series channels to be identified from a natural product source and will be useful as aprobe for studying potassium channel structure and the physiological role of such channels in target tissuesof interest.