Discovery of a novel activator of KCNQ1-KCNE1 K channel complexes.
KCNQ1 voltage-gated K(+) channels (Kv7.1) associate with the family of five KCNE peptides to form complexes with diverse gating properties and pharmacological sensitivities. The varied gating properties of the different KCNQ1-KCNE complexes enables the same K(+) channel to function in both excitable and non excitable tissues. Small molecule activators would be valuable tools for dissecting the gating mechanisms of KCNQ1-KCNE complexes; however, there are very few known activators of KCNQ1 channels and most are ineffective on the physiologically relevant KCNQ1-KCNE complexes. Here we show that a simple boronic acid, phenylboronic acid (PBA), activates KCNQ1/KCNE1 complexes co-expressed in Xenopus oocytes at millimolar concentrations. PBA shifts the voltage sensitivity of KCNQ1 channel complexes to favor the open state at negative potentials. Analysis of different-sized charge carriers revealed that PBA also targets the permeation pathway of KCNQ1 channels. Activation by the boronic acid moiety has some specificity for the Kv7 family members (KCNQ1, KCNQ2/3, and KCNQ4) since PBA does not activate Shaker or hERG channels. Furthermore, the commercial availability of numerous PBA derivatives provides a large class of compounds to investigate the gating mechanisms of KCNQ1-KCNE complexes.
Mruk
Karen
K
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
Kobertz
William R
WR
D000818:Animals; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004594:Electrophysiology / Q000379:methods; D005786:Gene Expression Regulation; D015640:Ion Channel Gating / Q000187:drug effects; D051657:KCNQ1 Potassium Channel / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D009865:Oocytes / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D014981:Xenopus
D001897:Boronic Acids; D018076:DNA, Complementary; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; D010455:Peptides; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; C010686:benzeneboronic acid