Mutations in the gene, encoding one of the major subunits of cardiac G-protein-gated inwardly rectifying K (GIRK) channels, have been recently linked to inherited forms of sinus node dysfunction. Here, the pathogenic mechanism of the W101C mutation underlying sinus bradycardia in a patient-derived cellular disease model of sinus node dysfunction (SND) was investigated. A human-induced pluripotent stem cell (hiPSCs) line of a mutation carrier was generated, and CRISPR/Cas9-based gene targeting was used to correct the familial mutation as a control line. Both cell lines were further differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed GIRK channels which underly the acetylcholine-regulated K current (I). hiPSC-CMs with the W101C mutation (hiPSC-CM) had a constitutively active I under baseline conditions; the application of carbachol was able to increase I, further indicating that not all available cardiac GIRK channels were open at baseline. Additionally, hiPSC-CM had a more negative maximal diastolic potential (MDP) and a slower pacing frequency confirming the bradycardic phenotype. Of note, the blockade of the constitutively active GIRK channel with XAF-1407 rescued the phenotype. These results provide further mechanistic insights and may pave the way for the treatment of SND patients with GIRK channel dysfunction.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10607318 | PMC |
http://dx.doi.org/10.3390/ijms242015290 | DOI Listing |
Neuropharmacology
January 2025
Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229, USA. Electronic address:
Kappa opioid receptors (KOR) expressed by peripheral pain-sensing neurons (nociceptors) are a promising target for development of effective and safer analgesics for inflammatory pain that are devoid of central nervous system adverse effects. Here we sought to delineate the signaling pathways that underlie peripheral KOR-mediated antinociception in adult male and female Sprague-Dawley rats. In an inflammatory model of pain, local intraplantar (i.
View Article and Find Full Text PDFJ Neurochem
January 2025
Molecular Horizons, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia.
GABA receptor (GABAR) activation is known to alleviate pain by reducing neuronal excitability, primarily through inhibition of high voltage-activated (HVA) calcium (Ca2.2) channels and potentiating G protein-coupled inwardly rectifying potassium (GIRK) channels. Although the analgesic properties of small molecules and peptides have been primarily tested on isolated murine dorsal root ganglion (DRG) neurons, emerging strategies to develop, study, and characterise human pluripotent stem cell (hPSC)-derived sensory neurons present a promising alternative.
View Article and Find Full Text PDFJ Nat Prod
January 2025
Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, University of South Carolina, Columbia, South Carolina 29208, United States.
Cannabidiol (CBD) is a natural product associated with a wide range of biological and therapeutic activities. Despite the widespread cultural acceptance of CBD as a medicinal agent, much remains to be determined regarding its precise mechanism(s) of action in treating multiple conditions. CBD has been shown to promiscuously interact with several neurological targets with varying affinities.
View Article and Find Full Text PDFBr J Pharmacol
January 2025
Department of Physiology and Pharmacology, School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Background And Purpose: The antiepileptic drug ethosuximide (ETX) suppresses epileptiform activity in a mouse model of GNB1 syndrome, caused by mutations in Gβ protein, likely through the inhibition of G-protein gated K (GIRK) channels. Here, we investigated the mechanism of ETX inhibition (block) of different GIRKs.
Experimental Approach: We studied ETX inhibition of GIRK channels expressed in Xenopus oocytes with or without their physiological activator, the G protein subunit dimer Gβγ.
Proc Natl Acad Sci U S A
January 2025
Laboratory of Molecular Neurobiology and Biophysics, The Rockefeller University, New York, NY 10065.
We examine the role of higher-order transient structures (HOTS) in M2R regulation of GIRK channels. Electron microscopic membrane protein location maps show that both proteins form HOTS that exhibit a statistical bias to be near each other. Theoretical calculations and electrophysiological measurements suggest that channel activity is isolated near larger M2R HOTS.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!