GABAB receptor-mediated modulation of sensory neuron excitability: Roles of CaV2.2, G-protein-coupled inwardly rectifying potassium (GIRK) channels, and hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels in human and mouse nociception
Date
2025
Authors
Brizuela, M.
Bony, A.R.
Garcia-Caraballo, S.
Adams, D.J.
Brierley, S.M.
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Experimental Physiology, 2025; 111(4):1-18
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Mariana Brizuela, Anuja R. Bony, Sonia Garcia-Caraballo, David J. Adams, Stuart M. Brierley
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Abstract
Chronic visceral pain is a key symptom of irritable bowel syndrome. Modulation of voltage-gated calcium and potassium channels by G protein-coupled receptors plays a key role in dampening nociceptive transmission. Both baclofen and the analgesic peptide α-conotoxin Vc1.1 activate GABAB receptors (GABABR), resulting in inhibition of CaV2.2 and CaV2.3 calcium channels to reduce colonic nociception. Recent studies have also shown that GABABR activation potentiates G-protein-coupled inwardly rectifying potassium (GIRK)-1/2 channels in mammalian sensory afferent neurons. In this study, we investigated the expression of these ion channel targets in rodent and human dorsal root ganglion (DRG) neurons, including those innervating the colon. We examined how CaV2.2 and GIRK channel antagonists, as well as a GIRK channel activator, influence the passive and active electrical properties of adult mouse DRG neurons. We also assessed the effects of α-conotoxin Vc1.1 on neuronal excitability in the presence of the selective CaV2.2 antagonist ω-conotoxin CVIE and the GIRK channel activator ML297. We further evaluated the impact of the GIRK channel antagonist tertiapin-Q on excitability in mouse colonic DRGs and afferents and explored the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Our findings demonstrate that both CaV2.2 inhibition and GIRK channel potentiation reduce excitability in mouse DRGs, likely mediating the antinociceptive effects of Vc1.1 and baclofen observed in vivo. However, GIRK channel potentiation appears to play only a limited role in modulating excitability in colon-innervating DRGs and colonic afferents. These findings suggest that neurons innervating different body regions use distinct mechanisms to regulate excitability and nociceptive signalling.
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© 2025 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.