Differential contributions of Ca V 2.2, GIRK, and HCN channel to the modulation of excitability by α-conotoxin Vc1.1 and baclofen in somatic and visceral sensory 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

Chronic visceral pain is a key symptom of irritable bowel syndrome (IBS). Modulation of voltage-dependent calcium and potassium channels by G protein-coupled receptors (GPCRs) plays a key role in dampening nociceptive transmission. Baclofen and the analgesic peptide α-conotoxin Vc1.1 both activate GABA B receptors (GABA B R), resulting in the inhibition of Ca V 2.2 and Ca V 2.3 calcium channels to reduce colonic nociception. Recent studies have also shown that GABA B R activation potentiates GIRK1/2 potassium 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 also examined how Ca V 2.2 and GIRK channel antagonists, as well as a GIRK channel activator, affect 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. We further evaluated the impact of the GIRK channel antagonist Tertiapin-Q on excitability in mouse colonic DRGs and colonic afferents and explored the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in regulating membrane excitability of colonic DRGs. Our findings demonstrate that both Ca V 2.2 inhibition and GIRK channel potentiation reduce excitability in mouse DRGs, likely mediating the analgesic effects of Vc1.1 and baclofen observed in vivo . However, our findings indicate that GIRK channel potentiation appears to play a limited role in modulating excitability in colon-innervating DRGs and colonic afferents. These findings suggest that neurons innervating different regions of the body employ distinct mechanisms to regulate neuronal excitability and nociceptive signaling.

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.

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

  • The analgesic peptide, α-conotoxin Vc1.1 reduces neuronal excitability by inhibiting Ca V 2.2 and potentiating GIRK channels.

  • However, potentiation of GIRK channels does not significantly affect the excitability in colon-innervating DRG neurons or colonic afferents.

  • Sensory neurons innervating different body regions utilize distinct mechanisms to regulate their excitability.

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  1. Version published to 10.1101/2025.03.21.644483 on bioRxiv