Contribution of Ca V 2.2 and GIRK1/2 channels to membrane excitability of rodent and human dorsal root ganglion neurons

  1. Mariana Brizuela
  2. Anuja R. Bony
  3. Sonia Garcia Caraballo
  4. David J. Adams
  5. Stuart M. Brierley
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Abstract

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 α-conotoxin Vc1.1 activate GABA B receptors, resulting in the inhibition of Ca V 2.2 and Ca V 2.3 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 Ca V 2.2 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 α-conotoxin Vc1.1 on neuronal excitability in the presence of the selective Ca V 2.2 antagonist ω-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 Ca V 2.2 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.

KEY POINTS SUMMARY

  • GABA B R1, Ca V 2.2, and GIRK1 are highly expressed in the thoracolumbar dorsal root ganglia (DRGs) of both mice and humans.

  • Ca V 2.2 inhibition and GIRK channel potentiation contribute to reduced neuronal excitability in mouse DRGs.

  • The analgesic peptide, α-conotoxin Vc1.1, exerts its effects by inhibiting Ca V 2.2 and potentiating GIRK channels in mouse DRGs.

  • Potentiation of GIRK channels does not significantly affect the excitability of colon-innervating DRGs or colonic afferents.

  • These findings suggest neurons innervating different regions of the body employ distinct mechanisms to regulate neuronal excitability.

Abstract Figure

Whole-cell patch-clamp recordings from mouse sensory neurons demonstrated that α-conotoxin Vc1.1 significantly reduces neuronal activity by inhibiting Ca V 2.2 and Ca V 2.3 and potentiating GIRK channels in ‘general’ mouse dorsal root ganglion (DRG) neurons, highlighting its dual role in modulating sensory neuron excitability.

Inhibition of GIRK channels with the antagonist Tertiapin-Q (TPQ) increased neuronal excitability; however, this effect was not observed in DRG neurons that innervate the mouse colon.

Inhibition of high voltage-activated calcium channels (Ca V 2.2) by the Ca V 2.2 antagonist CVIE and activation of the G protein-coupled inwardly rectifying potassium (GIRK) channels by the agonist ML297 both contribute to a reduction in neuronal excitability in ‘general’ mouse DRG neurons. Figure created with Biorender

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  1. Version published to 10.1101/2025.03.21.644483v1 on bioRxiv