When:
Monday, December 2, 2019
4:00 PM - 5:00 PM CT
Where: Ward Building, Room 5-230, 303 E. Chicago Avenue, Chicago, IL 60611 map it
Audience: Faculty/Staff - Student - Public - Post Docs/Docs - Graduate Students
Contact:
Lexi Nash
(312) 503-4893
Group: Department of Pharmacology Seminars
Category: Lectures & Meetings
Geoffrey W. Abbott, Ph.D.
Professor of Pharmacology, Physiology and Biophysics
University of California – Irvine
γ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in vertebrate CNS. The canonical action of GABA is via binding to neuronal GABA receptors (GABARs) to induce hyperpolarization by intrinsic (GABAA/CRs) or extrinsic (GABABRs) ion channel activation. Voltage-gated potassium channels KCNQ2-5, especially KCNQ2/3 heteromers, generate the neuronal M-current, another important hyperpolarizing force. Here, we discuss our recent finding that GABA and related metabolites directly activate KCNQ2/3 channels, and KCNQ2/3-dependently hyperpolarizes cells, with sensitivity comparable to the most sensitive α/β/γ GABAARs. We identified the M-channel GABA binding site as KCNQ3-W265, a position conserved for >500 million years in deuterostome clades but absent in protostomes and in cardiac-expressed KCNQ1. M-channel activation is a novel, unexpected mechanism for physiological and therapeutic inhibitory actions of GABA and analogues. This work has led to further discoveries in KCNQ channel pharmacology, including isolation of a potent KCNQ channel activator from cilantro. We also found that activation of the vascular-expressed KCNQ5 is a common mechanism for a variety of genetically and culturally diverse hypotensive botanical folk medicines. The implications of this work will be discussed with respect to KCNQ channel physiology, pharmacology and drug discovery.