Contribution of CaV2.2 and GIRK1/2 channels to membrane excitability of rodent and human dorsal root ganglion neurons
Modulation of voltage-dependent calcium and potassium channels by G protein-coupled receptors (GPCRs) plays a key role in reducing nociceptive transmission. Specifically, baclofen and the analgesic peptide -conotoxin Vc1.1 activate GABAB receptors, resulting in the inhibition of CaV2.2 and CaV2.3 calcium channels, as well as the potentiation of GIRK1/2 potassium channels in mammalian primary afferent neurons. In this study, we examined the expression of these key ion channel targets in rodent and human dorsal root ganglion (DRG) neurons. 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. Additionally, we assessed the effects of -conotoxin Vc1.1 on neuronal excitability in the presence of the selective CaV2.2 antagonist {omega}-conotoxin CVIE and the GIRK channel activator ML297. Furthermore, we evaluated how the GIRK channel antagonist Tertiapin-Q affects the excitability of mouse colonic DRGs and colonic afferents and explored the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in regulating the membrane excitability of colonic DRGs. Our findings suggest that both CaV2.2 inhibition and GIRK channel potentiation contribute to the reduction of neuronal excitability in mouse DRGs, mediating the analgesic effects of Vc1.1 and baclofen observed in vivo. However, our findings indicate that GIRK channel potentiation may have a limited role in the mechanisms underlying Vc1.1 and baclofen action in colon-innervating DRGs and colonic afferents.