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.
Ivermectin activates GIRK channels in a PIP2 -dependent, Gβγ -independent manner and an amino acid residue at the slide helix governs the activation.
Chen IS
,
Tateyama M
,
Fukata Y
,
Uesugi M
,
Kubo Y
.
???displayArticle.abstract???
KEY POINTS: Ivermectin (IVM) is a widely used antiparasitic drug in humans and pets which activates glutamate-gated Cl- channel in parasites. It is known that IVM binds to the transmembrane domains (TMs) of several ligand-gated channels, such as Cys-loop receptors and P2X receptors. We found that the G-protein-gated inwardly rectifying K+ (GIRK) channel, especially GIRK2, is activated by IVM directly in a Gβγ -independent manner, but the activation is dependent on phosphatidylinositol-4,5-biphosphate (PIP2 ). We identified a critical amino acid residue of GIRK2 for activation by IVM, Ile82, located in the slide helix between the TM1 and the N-terminal cytoplasmic tail domain (CTD). The results demonstrate that the TM-CTD interface in GIRK channel, rather than the TMs, governs IVM-mediated activation and provide us with novel insights on the mode of action of IVM in ion channels.
ABSTRACT: Ivermectin (IVM) is a widely used antiparasitic drug in humans and pets which activates glutamate-gated Cl- channel in parasites. It is also known that IVM binds to the transmembrane domains (TMs) of several ligand-gated channels, such as Cys-loop receptors and P2X receptors. In this study, we found that the G-protein-gated inwardly rectifying K+ (GIRK) channel is activated by IVM directly. Electrophysiological recordings in Xenopus oocytes revealed that IVM activates GIRK channel in a phosphatidylinositol-4,5-biphosphate (PIP2 )-dependent manner, and that the IVM-mediated GIRK activation is independent of Gβγ subunits. We found that IVM activates GIRK2 more efficiently than GIRK4. In cultured hippocampal neurons, we also observed that IVM activates native GIRK current. Chimeric and mutagenesis analyses identified an amino acid residue unique to GIRK2 among the GIRK family, Ile82, located in the slide helix between the TM1 and the N-terminal cytoplasmic tail domain (CTD), which is critical for the activation. The results demonstrate that the TM-CTD interface in GIRK channels, rather than the TMs, governs IVM-mediated activation. These findings provide us with novel insights on the mode of action of IVM in ion channels that could lead to identification of new pharmacophores which activate the GIRK channel.
Adelsberger,
Activation of rat recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptor by the insecticide ivermectin.
2000, Pubmed
Adelsberger,
Activation of rat recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptor by the insecticide ivermectin.
2000,
Pubmed
Aryal,
A discrete alcohol pocket involved in GIRK channel activation.
2009,
Pubmed
Barragry,
A review of the pharmacology and clinical uses of ivermectin.
1987,
Pubmed
Burkhart,
Ivermectin: an assessment of its pharmacology, microbiology and safety.
2000,
Pubmed
Campbell,
Ivermectin as an antiparasitic agent for use in humans.
1991,
Pubmed
Campbell,
Ivermectin: a potent new antiparasitic agent.
1983,
Pubmed
Clapham,
New roles for G-protein beta gamma-dimers in transmembrane signalling.
1993,
Pubmed
Cully,
Identification of a Drosophila melanogaster glutamate-gated chloride channel sensitive to the antiparasitic agent avermectin.
1996,
Pubmed
,
Xenbase
Du,
Glycine receptor mechanism elucidated by electron cryo-microscopy.
2015,
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
Fomkina,
Channel-forming properties of the neuropeptide preparation abamectin in bilayer lipid membranes.
2001,
Pubmed
Fukata,
Local palmitoylation cycles define activity-regulated postsynaptic subdomains.
2013,
Pubmed
González Canga,
The pharmacokinetics and metabolism of ivermectin in domestic animal species.
2009,
Pubmed
Grudzinska,
The beta subunit determines the ligand binding properties of synaptic glycine receptors.
2005,
Pubmed
Grundy,
Principles and standards for reporting animal experiments in The Journal of Physiology and Experimental Physiology.
2015,
Pubmed
Hansen,
Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.
2011,
Pubmed
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Hibino,
Inwardly rectifying potassium channels: their structure, function, and physiological roles.
2010,
Pubmed
Ho,
Molecular determinants for sodium-dependent activation of G protein-gated K+ channels.
1999,
Pubmed
,
Xenbase
Hopper,
Ivermectin toxicity in 17 collies.
2002,
Pubmed
Huang,
Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma.
1998,
Pubmed
,
Xenbase
Ikeda,
Genetic studies of avermectin biosynthesis in Streptomyces avermitilis.
1987,
Pubmed
Inanobe,
Characterization of G-protein-gated K+ channels composed of Kir3.2 subunits in dopaminergic neurons of the substantia nigra.
1999,
Pubmed
,
Xenbase
Ito,
On the mechanism of G protein beta gamma subunit activation of the muscarinic K+ channel in guinea pig atrial cell membrane. Comparison with the ATP-sensitive K+ channel.
1992,
Pubmed
Jelínkova,
Identification of P2X(4) receptor transmembrane residues contributing to channel gating and interaction with ivermectin.
2008,
Pubmed
Jin,
The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism.
2013,
Pubmed
Kaufmann,
ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice.
2013,
Pubmed
Kobayashi,
Ethanol opens G-protein-activated inwardly rectifying K+ channels.
1999,
Pubmed
,
Xenbase
Kofuji,
Evidence that neuronal G-protein-gated inwardly rectifying K+ channels are activated by G beta gamma subunits and function as heteromultimers.
1995,
Pubmed
,
Xenbase
Krapivinsky,
The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins.
1995,
Pubmed
,
Xenbase
Krause,
Ivermectin: a positive allosteric effector of the alpha7 neuronal nicotinic acetylcholine receptor.
1998,
Pubmed
,
Xenbase
Kubo,
Primary structure and functional expression of a rat G-protein-coupled muscarinic potassium channel.
1993,
Pubmed
,
Xenbase
Lesage,
Molecular properties of neuronal G-protein-activated inwardly rectifying K+ channels.
1995,
Pubmed
,
Xenbase
Lesage,
Cloning provides evidence for a family of inward rectifier and G-protein coupled K+ channels in the brain.
1994,
Pubmed
,
Xenbase
Lewohl,
G-protein-coupled inwardly rectifying potassium channels are targets of alcohol action.
1999,
Pubmed
,
Xenbase
Liao,
Heteromultimerization of G-protein-gated inwardly rectifying K+ channel proteins GIRK1 and GIRK2 and their altered expression in weaver brain.
1996,
Pubmed
Logothetis,
The beta gamma subunits of GTP-binding proteins activate the muscarinic K+ channel in heart.
,
Pubmed
Lovell,
Ivermectin and piperazine toxicoses in dogs and cats.
1990,
Pubmed
Lynagh,
Ivermectin binding sites in human and invertebrate Cys-loop receptors.
2012,
Pubmed
Lynagh,
A glycine residue essential for high ivermectin sensitivity in Cys-loop ion channel receptors.
2010,
Pubmed
Martin,
An electrophysiological preparation of Ascaris suum pharyngeal muscle reveals a glutamate-gated chloride channel sensitive to the avermectin analogue, milbemycin D.
1996,
Pubmed
Martin,
A patch-clamp study of effects of dihydroavermectin on Ascaris muscle.
1989,
Pubmed
McCavera,
An ivermectin-sensitive glutamate-gated chloride channel from the parasitic nematode Haemonchus contortus.
2009,
Pubmed
,
Xenbase
Meng,
The Molecular Mechanism of Opening the Helix Bundle Crossing (HBC) Gate of a Kir Channel.
2016,
Pubmed
Murata,
Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor.
2005,
Pubmed
,
Xenbase
Murata,
Depolarization activates the phosphoinositide phosphatase Ci-VSP, as detected in Xenopus oocytes coexpressing sensors of PIP2.
2007,
Pubmed
,
Xenbase
Nishida,
Crystal structure of a Kir3.1-prokaryotic Kir channel chimera.
2007,
Pubmed
Noma,
Relaxation of the ACh-induced potassium current in the rabbit sinoatrial node cell.
1978,
Pubmed
Reuveny,
Activation of the cloned muscarinic potassium channel by G protein beta gamma subunits.
1994,
Pubmed
,
Xenbase
Robertson,
Actions of anaesthetics and avermectin on GABAA chloride channels in mammalian dorsal root ganglion neurones.
1989,
Pubmed
Sakata,
Coupling of the phosphatase activity of Ci-VSP to its voltage sensor activity over the entire range of voltage sensitivity.
2011,
Pubmed
,
Xenbase
Schönrock,
Activation of Cl- channels by avermectin in rat cultured hippocampal neurons.
1993,
Pubmed
Shan,
Ivermectin, an unconventional agonist of the glycine receptor chloride channel.
2001,
Pubmed
Sigel,
Effect of avermectin B1a on chick neuronal gamma-aminobutyrate receptor channels expressed in Xenopus oocytes.
1987,
Pubmed
,
Xenbase
Silberberg,
Ivermectin Interaction with transmembrane helices reveals widespread rearrangements during opening of P2X receptor channels.
2007,
Pubmed
,
Xenbase
Su,
Novel cell-free high-throughput screening method for pharmacological tools targeting K+ channels.
2016,
Pubmed
Sui,
Activation of the atrial KACh channel by the betagamma subunits of G proteins or intracellular Na+ ions depends on the presence of phosphatidylinositol phosphates.
1998,
Pubmed
,
Xenbase
Whorton,
Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium.
2011,
Pubmed
,
Xenbase
Yow,
Naringin directly activates inwardly rectifying potassium channels at an overlapping binding site to tertiapin-Q.
2011,
Pubmed
,
Xenbase
Zeidner,
Redox-dependent gating of G protein-coupled inwardly rectifying K+ channels.
2001,
Pubmed
,
Xenbase
Zemkova,
Allosteric modulation of ligand gated ion channels by ivermectin.
2014,
Pubmed
Zheng,
Identification of two novel Drosophila melanogaster histamine-gated chloride channel subunits expressed in the eye.
2002,
Pubmed
