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

Abstract

BACKGROUND AND PURPOSE\nActivation of GIRK channels via G protein-coupled GABAB receptors (GABAB R) has been shown to attenuate nociceptive transmission. Analgesic α-conotoxin Vc1.1 has been shown to activate GABAB R resulting in inhibition of Cav2.2 and Cav2.3 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.\n\n\nEXPERIMENTAL APPROACH\nThe 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 GABAB 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.\n\n\nKEY RESULTS\nAnalgesic α-conotoxins Vc1.1, RgIA and PeIA potentiate inwardly-rectifying K+ currents in HEK293T cells recombinantly expressing human GIRK1/2 channels and GABAB R. GABAB R-dependent GIRK channel potentiation by Vc1.1 and baclofen occurs via a pertussis toxin-sensitive G protein and is inhibited by the selective GABAB R antagonist CGP 55845. In adult mouse dorsal root ganglion neurons, GABAB R-dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarizes the cell membrane potential and reduces excitability.\n\n\nCONCLUSIONS AND IMPLICATIONS\nThis is the first report of GIRK channel potentiation via allosteric α-conotoxin Vc1.1-GABAB R agonism leading to decreased neuronal excitability thus, potentially contributing to the analgesic effects of Vc1.1 and baclofen observed in vivo.