Multiple ion channels influence neuronal excitability, and these are often subject to modulation by neurotransmitters. Prominent among these are background K+ channels that are targeted for inhibition by neurotransmitters, leading to membrane depolarization and increased excitability. G protein-coupled receptors capable of mediating this effect have been identified for many transmitters (invariably those that couple via Gaq/n-family subunits), and it represents a predominant mechanism for slow synaptic excitation throughout the brain. The molecular identity of background K+ channels targeted for inhibition are unknown in most native systems, and the mechanisms of receptor-mediated channel inhibition remain obscure. Proposed research explores novel mechanisms and molecular substrates underlying Gaq-linked inhibition of background K+ channels. Our studies of cloned two-pore-domain background K+(K2P)channels - TASK-i (K2Ps) andTASK-3 (K2Pg) - has revealed a novel mechanismfor Gaq-mediated ion channel modulation. We find that TASK channel inhibition is independent of phospholipase C (PLC) activation and PI(4,5)P2 depletion, but instead requires Gaq interaction with the channels or with a closely-associated intermediary. Wepropose studies designed to identify molecular determinants that accountfor Gaq association and TASK channel inhibition, and to examine if this PLC- independent mechanism contributes to inhibition of other types of background K+ channels and their neuronal correlates by Gaq. Our published and preliminary work has identified TASK channels as substrates for background K+ currents in cholinergic neurons, specifically motoneurons and striatal interneurons, based on a constellation ofvoltage-dependent and pharmacological properties. This tentative identification requires verification. We propose to use newly available knockout mice to test definitively the TASKsubunit contributions to these native neuronal backgroundK+currents. Interesting preliminary data indicates that TASK currents are not targets for Gaq-mediated inhibition in striatal cholinergic interneurons. Rather, a novel Ch-activated background K+ channel is inhibited by Gaq-linked metabotropic receptors (mGluRs). Wepropose experiments to determine if the recently identified Slo2 channels account for this mGluR-sensitive channel, and to identify the relevant Gaq-mediated inhibitory mechanism. The following Specific Aims are proposed: [i] Establish mechanisms underlying PLC-independent modulation ofTASK and GIRK channels by Gaq subunits;[2] Identify background K+ channels in striatal cholinergic interneurons and elucidate mechanisms that contribute to Gaq-mediated activation. These experiments will characterize molecular substrates underlying native neuronal neurotransmitter-modulated background K+ currents and examine molecular mechanisms by which they are modulated.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS033583-15
Application #
7989385
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Silberberg, Shai D
Project Start
1995-02-01
Project End
2012-11-30
Budget Start
2010-12-01
Budget End
2012-11-30
Support Year
15
Fiscal Year
2011
Total Cost
$324,778
Indirect Cost
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Zhang, Haopeng; Dong, Hailong; Cilz, Nicholas I et al. (2016) Neurotensinergic Excitation of Dentate Gyrus Granule Cells via Gαq-Coupled Inhibition of TASK-3 Channels. Cereb Cortex 26:977-90
Vu, Michael T; Du, Guizhi; Bayliss, Douglas A et al. (2015) TASK Channels on Basal Forebrain Cholinergic Neurons Modulate Electrocortical Signatures of Arousal by Histamine. J Neurosci 35:13555-67
Lazarenko, Roman; Geisler, Jessica; Bayliss, Douglas et al. (2014) D-chiro-inositol glycan stimulates insulin secretion in pancreatic β cells. Mol Cell Endocrinol 387:1-7
Chiu, Yu-Hsin; Ravichandran, Kodi S; Bayliss, Douglas A (2014) Intrinsic properties and regulation of Pannexin 1 channel. Channels (Austin) 8:103-9
Morenilla-Palao, Cruz; Luis, Enoch; Fernández-Peña, Carlos et al. (2014) Ion channel profile of TRPM8 cold receptors reveals a role of TASK-3 potassium channels in thermosensation. Cell Rep 8:1571-82
Lohman, Alexander W; Weaver, Janelle L; Billaud, Marie et al. (2012) S-nitrosylation inhibits pannexin 1 channel function. J Biol Chem 287:39602-12
Guagliardo, Nick A; Yao, Junlan; Hu, Changlong et al. (2012) TASK-3 channel deletion in mice recapitulates low-renin essential hypertension. Hypertension 59:999-1005
Sandilos, Joanna K; Bayliss, Douglas A (2012) Physiological mechanisms for the modulation of pannexin 1 channel activity. J Physiol 590:6257-66
Sandilos, Joanna K; Chiu, Yu-Hsin; Chekeni, Faraaz B et al. (2012) Pannexin 1, an ATP release channel, is activated by caspase cleavage of its pore-associated C-terminal autoinhibitory region. J Biol Chem 287:11303-11
Lazarenko, Roman M; Stornetta, Ruth L; Bayliss, Douglas A et al. (2011) Orexin A activates retrotrapezoid neurons in mice. Respir Physiol Neurobiol 175:283-7

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