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Gaq modulation of neuronal K+ channels: novel mechanisms and targets

Summary

Principal Investigator: DOUGLAS BAYLISS
Affiliation: University of Virginia
Country: USA
Abstract: 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.
Funding Period: ----------------1995 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Inhibition of a background potassium channel by Gq protein alpha-subunits
    Xiangdong Chen
    Department of Pharmacology, University of Virginia, Charlottesville, 22908, USA
    Proc Natl Acad Sci U S A 103:3422-7. 2006
  2. pmc Physiological mechanisms for the modulation of pannexin 1 channel activity
    Joanna K Sandilos
    Department of Pharmacology, University of Virginia, Charlottesville, VA, USA
    J Physiol 590:6257-66. 2012
  3. pmc S-nitrosylation inhibits pannexin 1 channel function
    Alexander W Lohman
    Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908, USA
    J Biol Chem 287:39602-12. 2012
  4. pmc TASK-3 as a potential antidepressant target
    Anthony L Gotter
    Department of Neuroscience, Merck Research Laboratories, West Point, PA, USA
    Brain Res 1416:69-79. 2011
  5. pmc Orexin A activates retrotrapezoid neurons in mice
    Roman M Lazarenko
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, United States
    Respir Physiol Neurobiol 175:283-7. 2011
  6. pmc AMP-activated protein kinase inhibits TREK channels
    Orsolya Kréneisz
    Department of Physiology and Neurobiology, University of Connecticut, 75 N Eagleville Rd Unit 3156, Storrs Mansfield, CT 06269 9011, USA
    J Physiol 587:5819-30. 2009
  7. pmc Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but does not abolish glucose or pH responses of orexin/hypocretin neurons
    J A Gonzalez
    Department of Pharmacology, University of Cambridge, Cambridge CB2 1 PD, UK
    Eur J Neurosci 30:57-64. 2009
  8. pmc The neuroprotective impact of the leak potassium channel TASK1 on stroke development in mice
    Sven G Meuth
    University of Wurzburg, Department of Neurology, Wurzburg, Germany
    Neurobiol Dis 33:1-11. 2009
  9. ncbi Striatal cholinergic interneurons express a receptor-insensitive homomeric TASK-3-like background K+ current
    Allison P Berg
    Department of Pharmacology, 5015 Jordan Hall, University of Virginia, Charlottesville, VA 22908, USA
    J Neurophysiol 97:1546-52. 2007
  10. ncbi Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat
    Ruth L Stornetta
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 26:10305-14. 2006

Detail Information

Publications13

  1. pmc Inhibition of a background potassium channel by Gq protein alpha-subunits
    Xiangdong Chen
    Department of Pharmacology, University of Virginia, Charlottesville, 22908, USA
    Proc Natl Acad Sci U S A 103:3422-7. 2006
    ....
  2. pmc Physiological mechanisms for the modulation of pannexin 1 channel activity
    Joanna K Sandilos
    Department of Pharmacology, University of Virginia, Charlottesville, VA, USA
    J Physiol 590:6257-66. 2012
    ..Delineating the distinct mechanisms of Panx1 modulation that prevail in different physiological contexts provides the possibility that these channels, and ATP release, could ultimately be targeted in a context-dependent manner...
  3. pmc S-nitrosylation inhibits pannexin 1 channel function
    Alexander W Lohman
    Robert M Berne Cardiovascular Research Center, University of Virginia, Charlottesville, Virginia 22908, USA
    J Biol Chem 287:39602-12. 2012
    ..Taken together, these results indicate that S-nitrosylation of Panx1 at Cys-40 and Cys-346 inhibits Panx1 channel currents and ATP release...
  4. pmc TASK-3 as a potential antidepressant target
    Anthony L Gotter
    Department of Neuroscience, Merck Research Laboratories, West Point, PA, USA
    Brain Res 1416:69-79. 2011
    ..Together, these results support the TASK-3 channel to act as a therapeutic target for antidepressant action...
  5. pmc Orexin A activates retrotrapezoid neurons in mice
    Roman M Lazarenko
    Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, United States
    Respir Physiol Neurobiol 175:283-7. 2011
    ..These data support the idea that RTN neurons are a point of convergence for several groups of CNS neurons that contribute to respiratory chemoreflexes, now including serotonergic and orexinergic neurons...
  6. pmc AMP-activated protein kinase inhibits TREK channels
    Orsolya Kréneisz
    Department of Physiology and Neurobiology, University of Connecticut, 75 N Eagleville Rd Unit 3156, Storrs Mansfield, CT 06269 9011, USA
    J Physiol 587:5819-30. 2009
    ....
  7. pmc Deletion of TASK1 and TASK3 channels disrupts intrinsic excitability but does not abolish glucose or pH responses of orexin/hypocretin neurons
    J A Gonzalez
    Department of Pharmacology, University of Cambridge, Cambridge CB2 1 PD, UK
    Eur J Neurosci 30:57-64. 2009
    ..Our results support a novel role for TASK genes in enhancing neuronal excitability and promoting high-frequency firing, but suggest that TASK1/3 subunits are not essential for orexin cell responses to glucose and pH...
  8. pmc The neuroprotective impact of the leak potassium channel TASK1 on stroke development in mice
    Sven G Meuth
    University of Wurzburg, Department of Neurology, Wurzburg, Germany
    Neurobiol Dis 33:1-11. 2009
    ..In conclusion, our data provide evidence for an important role of functional TASK channels in limiting tissue damage during cerebral ischemia...
  9. ncbi Striatal cholinergic interneurons express a receptor-insensitive homomeric TASK-3-like background K+ current
    Allison P Berg
    Department of Pharmacology, 5015 Jordan Hall, University of Virginia, Charlottesville, VA 22908, USA
    J Neurophysiol 97:1546-52. 2007
    ....
  10. ncbi Expression of Phox2b by brainstem neurons involved in chemosensory integration in the adult rat
    Ruth L Stornetta
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 26:10305-14. 2006
    ..The presence of Phox2b in this circuit and its apparent absence from the respiratory CPG could explain why Phox2b mutations disrupt breathing automaticity during sleep without causing major impairment of respiration during waking...
  11. ncbi TASK-like conductances are present within hippocampal CA1 stratum oriens interneuron subpopulations
    Christine L Torborg
    Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA
    J Neurosci 26:7362-7. 2006
    ..These data suggest that TASK-like conductances are more prevalent in inhibitory interneurons than previously supposed...
  12. ncbi Purinergic P2 receptors modulate excitability but do not mediate pH sensitivity of RTN respiratory chemoreceptors
    Daniel K Mulkey
    Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA
    J Neurosci 26:7230-3. 2006
    ..Therefore, we conclude that purinergic signaling can modulate RTN neuron activity but does not mediate the pH sensing intrinsic to these central respiratory chemoreceptors...
  13. ncbi D-chiro-inositol glycan stimulates insulin secretion in pancreatic β cells
    Roman Lazarenko
    Department of Pharmacology, University of Virginia Health System, Charlottesville, VA, United States
    Mol Cell Endocrinol 387:1-7. 2014
    ..In conclusion, the present study identifies a novel mechanism involving PP2C in regulating KATP channel activity and consequently insulin secretion. ..