A novel, rapid, inhibitory effect of insulin on α1β2γ2s γ-aminobutyric acid type A receptors

In the CNS, GABA and insulin seem to contribute to similar processes, including neuronal survival; learning and reward; and energy balance and food intake. It is likely then that insulin and GABA may interact, perhaps at the GABA(A) receptor. One such interaction has already been described IQ. Wan, Z.G. Xiong, H.Y. Man, C.A. Ackerley, J. Braunton, W.Y. Lu, LE. Becker, J.F. MacDonald, Y.T Wang, Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin, Nature 388 (1997) 686-690]; in it a micromolar concentration of insulin causes the insertion of GABAA receptors into the cell membrane, increasing GABA current. l have discovered another effect of insulin on GABAA currents. Using a receptor isoform, alpha(1)beta(2)gamma(2s) that is the likely main neuronal GABAA isoform expressed recombinantly in Xenopus oocytes, insulin inhibits GABA-induced current when applied simultaneously with low concentrations of GABA. Insulin will significantly inhibit currents induced by EC30-50 concentrations of GABA by about 38%. Insulin is potent in this effect; IC50 of insulin was found to be about 4.3 x 10(-10) M. The insulin effect on the GABA dose responses looked like that of an antagonist similar to bicuculline or beta-carbolines. However, an effect of phosphorylation on the GABAA receptor from the insulin receptor signal transduction pathway cannot yet be dismissed. (C) 2008 Elsevier Ireland Ltd. All rights reserved.