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

Abstract

Activation of G protein-coupled inwardly rectifying potassium (GIRK or Kir3) channels leads to membrane hyperpolarization and dampening of neuronal excitability. Here we show that the analgesic -conotoxin Vc1.1 potentiates inwardly rectifying K+ currents (IKir) mediated through native and recombinant GIRK1/2 channels by activation of the G protein-coupled GABAB receptor (GABABR) via a Pertussis toxin (PTX)-sensitive G protein. Recombinant co-expression of human GIRK1/2 subunits and GABABR in HEK293T cells resulted in a Ba2+-sensitive IKir potentiated by baclofen and Vc1.1 which was inhibited by PTX, intracellular GDP-{beta}-S, or the GABABR-selective antagonist CGP 55845. In adult mouse DRG neurons, GABABR-dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarizes the cell resting membrane potential with concomitant reduction of excitability consistent with Vc1.1 and baclofen analgesic effects in vivo. This study provides new insight into Vc1.1 as an allosteric agonist for GABABR-mediated potentiation of GIRK channels and may aid in the development of novel non-opioid treatments for chronic pain.