Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2010 Dec 31;28553:41290-9. doi: 10.1074/jbc.M110.178541.
Show Gene links
Show Anatomy links
G protein {beta}{gamma} gating confers volatile anesthetic inhibition to Kir3 channels.
Styer AM, Mirshahi UL, Wang C, Girard L, Jin T, Logothetis DE, Mirshahi T.
???displayArticle.abstract???
G protein-activated inwardly rectifying potassium (GIRK or Kir3) channels are directly gated by the βγ subunits of G proteins and contribute to inhibitory neurotransmitter signaling pathways. Paradoxically, volatile anesthetics such as halothane inhibit these channels. We find that neuronal Kir3 currents are highly sensitive to inhibition by halothane. Given that Kir3 currents result from increased Gβγ available to the channels, we asked whether reducing available Gβγ to the channel would adversely affect halothane inhibition. Remarkably, scavenging Gβγ using the C-terminal domain of β-adrenergic receptor kinase (cβARK) resulted in channel activation by halothane. Consistent with this effect, channel mutants that impair Gβγ activation were also activated by halothane. A single residue, phenylalanine 192, occupies the putative Gβγ gate of neuronal Kir3.2 channels. Mutation of Phe-192 at the gate to other residues rendered the channel non-responsive, either activated or inhibited by halothane. These data indicated that halothane predominantly interferes with Gβγ-mediated Kir3 currents, such as those functioning during inhibitory synaptic activity. Our report identifies the molecular correlate for anesthetic inhibition of Kir3 channels and highlights the significance of these effects in modulating neurotransmitter-mediated inhibitory signaling.
Andres-Enguix,
Determinants of the anesthetic sensitivity of two-pore domain acid-sensitive potassium channels: molecular cloning of an anesthetic-activated potassium channel from Lymnaea stagnalis.
2007, Pubmed
Andres-Enguix,
Determinants of the anesthetic sensitivity of two-pore domain acid-sensitive potassium channels: molecular cloning of an anesthetic-activated potassium channel from Lymnaea stagnalis.
2007,
Pubmed Aryal,
A discrete alcohol pocket involved in GIRK channel activation.
2009,
Pubmed Bertaccini,
The common chemical motifs within anesthetic binding sites.
2007,
Pubmed Blednov,
A pervasive mechanism for analgesia: activation of GIRK2 channels.
2003,
Pubmed Campagna,
Mechanisms of actions of inhaled anesthetics.
2003,
Pubmed Carman,
Mutational analysis of Gbetagamma and phospholipid interaction with G protein-coupled receptor kinase 2.
2000,
Pubmed Chen,
Constitutively active G-protein-gated inwardly rectifying K+ channels in dendrites of hippocampal CA1 pyramidal neurons.
2005,
Pubmed Chen,
Inhibition of a background potassium channel by Gq protein alpha-subunits.
2006,
Pubmed Chiara,
Identification of nicotinic acetylcholine receptor amino acids photolabeled by the volatile anesthetic halothane.
2003,
Pubmed Du,
Characteristic interactions with phosphatidylinositol 4,5-bisphosphate determine regulation of kir channels by diverse modulators.
2004,
Pubmed
,
Xenbase Eger,
Relevant concentrations of inhaled anesthetics for in vitro studies of anesthetic mechanisms.
2001,
Pubmed Eger,
Characteristics of anesthetic agents used for induction and maintenance of general anesthesia.
2004,
Pubmed Finley,
betaL-betaM loop in the C-terminal domain of G protein-activated inwardly rectifying K(+) channels is important for G(betagamma) subunit activation.
2004,
Pubmed
,
Xenbase Franks,
Which molecular targets are most relevant to general anaesthesia?
1998,
Pubmed Franks,
The TREK K2P channels and their role in general anaesthesia and neuroprotection.
2004,
Pubmed Franks,
Molecular targets underlying general anaesthesia.
2006,
Pubmed Guy-David,
PIP2--the master key.
2007,
Pubmed He,
Identification of a potassium channel site that interacts with G protein betagamma subunits to mediate agonist-induced signaling.
1999,
Pubmed He,
Identification of critical residues controlling G protein-gated inwardly rectifying K(+) channel activity through interactions with the beta gamma subunits of G proteins.
2002,
Pubmed Hemmings,
Emerging molecular mechanisms of general anesthetic action.
2005,
Pubmed Huang,
Binding of the G protein betagamma subunit to multiple regions of G protein-gated inward-rectifying K+ channels.
1997,
Pubmed Ivanina,
Mapping the Gbetagamma-binding sites in GIRK1 and GIRK2 subunits of the G protein-activated K+ channel.
2003,
Pubmed
,
Xenbase Jelacic,
Functional and biochemical evidence for G-protein-gated inwardly rectifying K+ (GIRK) channels composed of GIRK2 and GIRK3.
2000,
Pubmed Jin,
The (beta)gamma subunits of G proteins gate a K(+) channel by pivoted bending of a transmembrane segment.
2002,
Pubmed
,
Xenbase Koyrakh,
Molecular and cellular diversity of neuronal G-protein-gated potassium channels.
2005,
Pubmed Kulik,
Compartment-dependent colocalization of Kir3.2-containing K+ channels and GABAB receptors in hippocampal pyramidal cells.
2006,
Pubmed Lazarenko,
Anesthetic activation of central respiratory chemoreceptor neurons involves inhibition of a THIK-1-like background K(+) current.
2010,
Pubmed Leaney,
Contribution of Kir3.1, Kir3.2A and Kir3.2C subunits to native G protein-gated inwardly rectifying potassium currents in cultured hippocampal neurons.
2003,
Pubmed Lerma,
In vivo determination of extracellular concentration of amino acids in the rat hippocampus. A method based on brain dialysis and computerized analysis.
1986,
Pubmed Lewohl,
G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action.
1999,
Pubmed
,
Xenbase Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase Logothetis,
The beta gamma subunits of GTP-binding proteins activate the muscarinic K+ channel in heart.
,
Pubmed Lopes,
Actions of general anaesthetics and arachidonic pathway inhibitors on K+ currents activated by volatile anaesthetics and FMRFamide in molluscan neurones.
1998,
Pubmed Lüscher,
Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease.
2010,
Pubmed Lüscher,
G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons.
1997,
Pubmed Marker,
Hyperalgesia and blunted morphine analgesia in G protein-gated potassium channel subunit knockout mice.
2002,
Pubmed Marker,
Distinct populations of spinal cord lamina II interneurons expressing G-protein-gated potassium channels.
2006,
Pubmed Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase Milovic,
The sensitivity of G protein-activated K+ channels toward halothane is essentially determined by the C terminus.
2004,
Pubmed
,
Xenbase Minami,
Sites of volatile anesthetic action on kainate (Glutamate receptor 6) receptors.
1998,
Pubmed Mirshahi,
G beta gamma and KACh: old story, new insights.
2003,
Pubmed Mirshahi,
Gbeta residues that do not interact with Galpha underlie agonist-independent activity of K+ channels.
2002,
Pubmed
,
Xenbase Mitrovic,
Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences.
2003,
Pubmed Nishida,
Crystal structure of a Kir3.1-prokaryotic Kir channel chimera.
2007,
Pubmed Nishida,
Structural basis of inward rectification: cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 A resolution.
2002,
Pubmed Patel,
Inhalational anesthetics activate two-pore-domain background K+ channels.
1999,
Pubmed Reuveny,
Activation of the cloned muscarinic potassium channel by G protein beta gamma subunits.
1994,
Pubmed
,
Xenbase Ronald,
Ethanol inhibition of N-methyl-D-aspartate receptors is reduced by site-directed mutagenesis of a transmembrane domain phenylalanine residue.
2001,
Pubmed
,
Xenbase Sadja,
Graded contribution of the Gbeta gamma binding domains to GIRK channel activation.
2002,
Pubmed
,
Xenbase Schreibmayer,
Voltage clamping of Xenopus laevis oocytes utilizing agarose-cushion electrodes.
1994,
Pubmed
,
Xenbase Signorini,
Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2.
1997,
Pubmed Sobolevsky,
X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor.
2009,
Pubmed Sodickson,
Neurotransmitter activation of inwardly rectifying potassium current in dissociated hippocampal CA3 neurons: interactions among multiple receptors.
1998,
Pubmed Sodickson,
GABAB receptor-activated inwardly rectifying potassium current in dissociated hippocampal CA3 neurons.
1996,
Pubmed Talley,
Modulation of TASK-1 (Kcnk3) and TASK-3 (Kcnk9) potassium channels: volatile anesthetics and neurotransmitters share a molecular site of action.
2002,
Pubmed Tao,
Crystal structure of the eukaryotic strong inward-rectifier K+ channel Kir2.2 at 3.1 A resolution.
2009,
Pubmed
,
Xenbase Torrecilla,
G-protein-gated potassium channels containing Kir3.2 and Kir3.3 subunits mediate the acute inhibitory effects of opioids on locus ceruleus neurons.
2002,
Pubmed Vivaudou,
Probing the G-protein regulation of GIRK1 and GIRK4, the two subunits of the KACh channel, using functional homomeric mutants.
1997,
Pubmed
,
Xenbase Weigl,
G protein-gated inwardly rectifying potassium channels are targets for volatile anesthetics.
2001,
Pubmed
,
Xenbase Yamakura,
Differential effects of general anesthetics on G protein-coupled inwardly rectifying and other potassium channels.
2001,
Pubmed
,
Xenbase Yi,
Yeast screen for constitutively active mutant G protein-activated potassium channels.
2001,
Pubmed
,
Xenbase Zhang,
Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions.
1999,
Pubmed
,
Xenbase
