Analgesic α-conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABAB receptors and reduce neuroexcitability

Background and Purpose: Activation of GIRK channels via G protein-coupled GABA(B) receptors has been shown to attenuate nociceptive transmission. The analgesic alpha-conotoxin Vc1.1 activates GABA(B) receptors resulting in inhibition of Ca-v 2.2 and Ca-v 2.3 channels in mammalian primary afferent neurons. Here, we investigated the effects of analgesic alpha-conotoxins on recombinant and native GIRK-mediated K-1 currents and on neuronal excitability. Experimental Approach: The effects of analgesic alpha-conotoxins, Vc1.1, RgIA, and PeIA, were investigated on inwardly-rectifying K+ currents in HEK293T cells recombinantly alpha-expressing either heteromeric human GIRK1/2 or homomeric GIRK2 subunits, with GABA(B) receptors. The effects of alpha-conotoxin Vc1.1 and baclofen were studied on GIRK-mediated K+ currents and the passive and active electrical properties of adult mouse dorsal root ganglion neurons. Key Results: Analgesic alpha-conotoxins Vc1.1, RgIA, and PelA potentiate inwardly-rectifying K+ currents in HEK293T cells recombinantly expressing human GIRK1/2 channels and GABA(B) receptors. GABA(B) receptor-dependent GIRK channel potentiation by Vc1.1 and baclofen occurs via a pertussis toxin-sensitive G protein and is inhibited by the selective GABA(B) receptor antagonist CGP 55845. In adult mouse dorsal root ganglion neurons, GABA(B) receptor-dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarizes the cell membrane potential and reduces excitability. Conclusions and Implications: This is the first report of GIRK channel potentiation via allosteric alpha-conotoxin Vc1.1-GABA(B) receptor agonism, leading to decreased neuronal excitability. Such action potentially contributes to the analgesic effects of Vc1.1 and baclofen observed in vivo.

Automated summary

This study is the first to report the potentiation of GIRK channels via allosteric alpha-conotoxin Vc1.1-GABA(B) receptor agonism, leading to decreased neuronal excitability. This finding contributes to the understanding of the analgesic effects of Vc1.1 and baclofen in vivo.