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

Background And Purpose: Activation of GIRK channels via G protein-coupled GABA receptors has been shown to attenuate nociceptive transmission. The analgesic α-conotoxin Vc1.1 activates GABA receptors resulting in inhibition of Ca 2.2 and Ca 2.3 channels in mammalian primary afferent neurons. Here, we investigated the effects of analgesic α-conotoxins on recombinant and native GIRK-mediated K currents and on neuronal excitability.

Experimental Approach: The effects of analgesic α-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 receptors. The effects of α-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 α-conotoxins Vc1.1, RgIA, and PeIA potentiate inwardly-rectifying K currents in HEK293T cells recombinantly expressing human GIRK1/2 channels and GABA receptors. GABA 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 receptor antagonist CGP 55845. In adult mouse dorsal root ganglion neurons, GABA 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 α-conotoxin Vc1.1-GABA receptor agonism, leading to decreased neuronal excitability. Such action potentially contributes to the analgesic effects of Vc1.1 and baclofen observed in vivo.