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+ 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 co-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 10 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

The study shows that analgesic alpha-conotoxins potentiate GIRK channels via GABA(B) receptor-dependent mechanisms, leading to decreased neuronal excitability.