Comparing an effect of insulin on GABA‐mediated current at a “neuronal” and a “pancreatic” isoform of the GABA‐A receptor

GABA A receptors have been localized to the brain and pancreas. In the CNS, GABA is the main inhibitory neurotransmitter, and, with insulin may be involved in pathways controlling hunger. In the pancreas, GABA is synthesized and co‐released with insulin from β cells. GABA binds at GABA A receptors on α cells where it modulates glucagon release. The GABA‐insulin interactions allow for the possibility that insulin could affect GABA‐mediated currents in both organs. The main neuronal (α 1 β 2 γ 2S ) or main pancreatic (α 4 β 3 γ 1 ) isoform of GABA A receptors were expressed in Xenopus oocytes clamped at −60 mV. Currents were whole cell currents obtained by two‐electrode voltage clamp. Stable control (no insulin) GABA‐induced currents were compared to currents induced by the same concentration of GABA in the presence of insulin. At the α 1 β 2 γ 2S isoform, currents induced by saturating GABA were not affected; however, at a submaximal GABA concentration, insulin inhibited currents approximately 45%, with an IC 50 in the 10 −9 to 10 −10 range. At the α 4 β 3 γ 1 isoform, currents induced by saturating GABA were inhibited about 50%; submaximal currents were also inhibited about 55% with an IC 50 in the 10 −9 to 10 −10 range. It is unknown if this is a direct effect of insulin on GABA A receptors, or due to receptor modification by phosphorylation perhaps through the insulin receptor signal transduction pathway. Support contributed by WSSU RIP and NIH.