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
2024 Mar 24;3005:107219. doi: 10.1016/j.jbc.2024.107219.
Show Gene links
Show Anatomy links
Structural determinants of the direct inhibition of GIRK channels by Sigma-1 receptor antagonist.
Liu C
,
Chen IS
,
Tateyama M
,
Kubo Y
.
???displayArticle.abstract???
G-protein-gated inward rectifier K+ (GIRK) channels play a critical role in the regulation of the excitability of cardiomyocytes and neurons and include GIRK1, GIRK2, GIRK3 and GIRK4 subfamily members. BD1047 dihydrobromide (BD1047) is one of the representative antagonists of the multifunctional Sigma-1 receptor (S1R). In the analysis of the effect of BD1047 on the regulation of Gi-coupled receptors by S1R using GIRK channel as an effector, we observed that BD1047, as well as BD1063, directly inhibited GIRK currents even in the absence of S1R and in a voltage-independent manner. Thus, we aimed to clarify the effect of BD1047 on GIRK channels and identify the structural determinants. By electrophysiological recordings in Xenopus oocytes, we observed that BD1047 directly inhibited GIRK channel currents, producing a much stronger inhibition of GIRK4 compared to GIRK2. It also inhibited ACh-induced native GIRK current in isolated rat atrial myocytes. Chimeric and mutagenesis studies of GIRK2 and GIRK4 combined with molecular docking analysis demonstrated the importance of Leu77 and Leu84 within the cytoplasmic, proximal N-terminal region and Glu147 within the pore-forming region of GIRK4 for inhibition by BD1047. The activator of GIRK channels, ivermectin, competed with BD1047 at Leu77 on GIRK4. This study provides us with a novel inhibitor of GIRK channels and information for developing pharmacological treatments for GIRK4-associated diseases.
Bodhinathan,
Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels.
2013,
Pubmed
Carmeliet,
Desensitization of the acetylcholine-induced increase of potassium conductance in rabbit cardiac Purkinje fibres.
1986,
Pubmed
Chen,
Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin.
2018,
Pubmed
Chen,
Licorice metabolite 18β-glycyrrhetinic acid activates G protein-gated inwardly rectifying K+ channels.
2024,
Pubmed
,
Xenbase
Chen,
Non-sedating antihistamines block G-protein-gated inwardly rectifying K+ channels.
2019,
Pubmed
,
Xenbase
Chen,
Ivermectin activates GIRK channels in a PIP2 -dependent, Gβγ -independent manner and an amino acid residue at the slide helix governs the activation.
2017,
Pubmed
,
Xenbase
Chen,
RGS4 regulates partial agonism of the M2 muscarinic receptor-activated K+ currents.
2014,
Pubmed
,
Xenbase
Choi,
Sigma-1 receptor increases intracellular calcium in cultured astrocytes and contributes to mechanical allodynia in a model of neuropathic pain.
2022,
Pubmed
Clapham,
New roles for G-protein beta gamma-dimers in transmembrane signalling.
1993,
Pubmed
Corey,
Identification of native atrial G-protein-regulated inwardly rectifying K+ (GIRK4) channel homomultimers.
1998,
Pubmed
Cui,
Kir Channel Molecular Physiology, Pharmacology, and Therapeutic Implications.
2021,
Pubmed
Cui,
A novel small-molecule selective activator of homomeric GIRK4 channels.
2022,
Pubmed
Dobrev,
The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation.
2005,
Pubmed
Hibino,
Inwardly rectifying potassium channels: their structure, function, and physiological roles.
2010,
Pubmed
Ho,
Molecular mechanism for sodium-dependent activation of G protein-gated K+ channels.
1999,
Pubmed
,
Xenbase
Huang,
Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma.
1998,
Pubmed
,
Xenbase
Jeremic,
Therapeutic potential of targeting G protein-gated inwardly rectifying potassium (GIRK) channels in the central nervous system.
2021,
Pubmed
Jin,
Mechanisms of inward-rectifier K+ channel inhibition by tertiapin-Q.
1999,
Pubmed
,
Xenbase
Kanjhan,
Tertiapin-Q blocks recombinant and native large conductance K+ channels in a use-dependent manner.
2005,
Pubmed
,
Xenbase
Kobayashi,
Inhibition of G protein-activated inwardly rectifying K+ channels by different classes of antidepressants.
2011,
Pubmed
,
Xenbase
Kobayashi,
Inhibition by various antipsychotic drugs of the G-protein-activated inwardly rectifying K(+) (GIRK) channels expressed in xenopus oocytes.
2000,
Pubmed
,
Xenbase
Kotajima-Murakami,
GIRK Channels as Candidate Targets for the Treatment of Substance Use Disorders.
2022,
Pubmed
Kourrich,
The sigma-1 receptor: roles in neuronal plasticity and disease.
2012,
Pubmed
Kovoor,
Evaluation of the role of I(KACh) in atrial fibrillation using a mouse knockout model.
2001,
Pubmed
Krapivinsky,
The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins.
1995,
Pubmed
,
Xenbase
Kubo,
Primary structure and functional expression of a rat G-protein-coupled muscarinic potassium channel.
1993,
Pubmed
,
Xenbase
Kubo,
Identification of domains of the cardiac inward rectifying K+ channel, CIR, involved in the heteromultimer formation and in the G-protein gating.
1996,
Pubmed
,
Xenbase
Kurachi,
Short-term desensitization of muscarinic K+ channel current in isolated atrial myocytes and possible role of GTP-binding proteins.
1987,
Pubmed
Lesage,
Cloning provides evidence for a family of inward rectifier and G-protein coupled K+ channels in the brain.
1994,
Pubmed
,
Xenbase
Logothetis,
The beta gamma subunits of GTP-binding proteins activate the muscarinic K+ channel in heart.
NULL,
Pubmed
Matsumoto,
Characterization of two novel sigma receptor ligands: antidystonic effects in rats suggest sigma receptor antagonism.
1995,
Pubmed
Mavlyutov,
The sigma-1 receptor is enriched in postsynaptic sites of C-terminals in mouse motoneurons. An anatomical and behavioral study.
2010,
Pubmed
Reynolds,
Ethanol Stimulates Endoplasmic Reticulum Inositol Triphosphate and Sigma Receptors to Promote Withdrawal-Associated Loss of Neuron-Specific Nuclear Protein/Fox-3.
2016,
Pubmed
Roh,
Intrathecal injection of the sigma(1) receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain.
2008,
Pubmed
Skuza,
Effect of BD 1047, a sigma1 receptor antagonist, in the animal models predictive of antipsychotic activity.
2006,
Pubmed
Su,
The Sigma-1 Receptor as a Pluripotent Modulator in Living Systems.
2016,
Pubmed
Su,
The sigma-1 receptor chaperone as an inter-organelle signaling modulator.
2010,
Pubmed
Wydeven,
Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297.
2014,
Pubmed
Yow,
Naringin directly activates inwardly rectifying potassium channels at an overlapping binding site to tertiapin-Q.
2011,
Pubmed
,
Xenbase