Neuronal G protein-gated K⁺ channels

Abstract

G protein-gated inwardly rectifying K+ (GIRK/Kir3) channels exert a critical inhibitory influence on neurons. Neuronal GIRK channels mediate the G protein-dependent, direct/postsynaptic inhibitory effect of many neurotransmitters including γ-aminobutyric acid (GABA), serotonin, dopamine, adenosine, somatostatin, and enkephalin. In addition to their complex regulation by G proteins, neuronal GIRK channel activity is sensitive to PIP2, phosphorylation, regulator of G protein signaling (RGS) proteins, intracellular Na+ and Ca2+, and cholesterol. The application of genetic and viral manipulations in rodent models, together with recent progress in the development of GIRK channel modulators, has increased our understanding of the physiological and behavioral impact of neuronal GIRK channels. Work in rodent models has also revealed that neuronal GIRK channel activity is modified, transiently or persistently, by various stimuli including exposure drugs of abuse, changes in neuronal activity patterns, and aversive experience. A growing body of preclinical and clinical evidence suggests that dysregulation of GIRK channel activity contributes to neurological diseases and disorders. The primary goals of this review are to highlight fundamental principles of neuronal GIRK channel biology, mechanisms of GIRK channel regulation and plasticity, the nascent landscape of GIRK channel pharmacology, and the potential relevance of GIRK channels to the pathophysiology and treatment of neurological diseases and disorders.

Epilepsy in a mouse model of GNB1 encephalopathy arises from altered potassium (GIRK) channel signaling and is alleviated by a GIRK inhibitor

“…GIRK channels are essential regulators of neuronal excitability, mainly through neurotransmitter-induced postsynaptic prolonged IPSPs, and in some cases presynaptically, by inhibiting neurotransmitter release (Thompson et al, 1993 ; Lüscher and Slesinger, 2010 ; Luo et al, 2022 ). In many neuronal subtypes, GIRKs exhibit basal activity (Chen and Johnston, 2005 ; Wiser et al, 2006 ; Farhy Tselnicker et al, 2014 ) that regulates dendritic integration (Malik and Johnston, 2017 ) and, less prominently, intrinsic excitability [e.g., (Torrecilla et al, 2013 ; Prytkova et al, 2023 ), consistent with our results].…”

“…G βγ directly regulates neuronal excitability via several pathways: inhibition of voltage-gated calcium channels (Ikeda, 1996 ; Dolphin, 1998 ; Zamponi and Currie, 2013 ), activation of postsynaptic G protein-coupled inwardly rectifying potassium (GIRK) channels (Dascal, 1997 ; Lüscher and Slesinger, 2010 ; Malik and Johnston, 2017 ; Luo et al, 2022 ), and inhibition of vesicle release through interactions with the SNARE complex (Yoon et al, 2007 ; Zurawski et al, 2017 ). The breadth and complexity of G βγ -mediated signaling pathways thus represent a significant challenge to the understanding of GNB1-related disease mechanisms.…”

GABA excitatory actions in cerebrospinal-fluid contacting neurones of adult mouse spinal cord

“…We further investigated the mechanisms underlying the lack of GABA B receptors-dependent K + currents, assuming that GIRK channels are not expressed in spinal CSF-cNs. To test this hypothesis, we applied on spinal CSF-cNs ML297, a direct and selective activator of GIRK1/2 channels, the most abundant neuronal GIRK channels (Gonzalez et al ., 2018; Kimura et al ., 2020; Luo et al ., 2022). However, ML297 failed to elicit an increase in the holding currents in CSF-cNs ( Fig.…”

“…As functional GABA B -Rs are present in CSF-cNs (Margeta-Mitrovic et al ., 1999; Jurčić et al ., 2019), one could suggest that the absence of GIRK currents in spinal CSF-cNs results from the lack of GIRK channels expression. However, even though heterotetramers GIRK channels containing GIRK1 and GIRK2 subunits predominate in the CNS, we cannot exclude the expression in CSF-cNs of GIRK channels assembled with other subunits such as GIRK3 or GIRK4 (Luo et al ., 2022). As pharmacological agents that selectively activate GIRK3 or GIRK4-containing channels are missing, dedicated experiments using immunostainings or transcriptomic analysis will address this eventuality.…”

Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling

“…This is exemplified in the case of Gβγ gating of K + flux through G protein–gated inwardly rectifying potassium (GIRK) channels ( 9 ). The GPCR–GIRK signaling axis is finely tuned by proteins that either promote or reduce Gβγ availability ( 10 ), with one example pertaining to the binding of Gβγ by certain potassium channel tetramerization domain (KCTD) proteins ( 11 , 12 ).…”