A novel, rapid, inhibitory effect of insulin on alpha1beta2gamma2s gamma-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 [Q. Wan, Z.G. Xiong, H.Y. Man, C.A. Ackerley, J. Braunton, W.Y. Lu, L.E. 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 GABA(A) receptors into the cell membrane, increasing GABA current. I have discovered another effect of insulin on GABA(A) currents. Using a receptor isoform, alpha(1)beta(2)gamma(2s) that is the likely main neuronal GABA(A) 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 EC(30-50) concentrations of GABA by about 38%. Insulin is potent in this effect; IC(50) 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 GABA(A) receptor from the insulin receptor signal transduction pathway cannot yet be dismissed.
Williams
Daniel B
DB
Department of Life Sciences, Winston-Salem St. University, 601 Martin Luther King Jr Dr, WBA 402, Winston-Salem, NC 27110, United States. williamsdb@wssu.edu
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018756:GABA Antagonists / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D007328:Insulin / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D008845:Microinjections; D009865:Oocytes; D018408:Patch-Clamp Techniques; D051381:Rats; D011963:Receptors, GABA-A / Q000502:physiology*; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002243:Carbolines; D018756:GABA Antagonists; D007004:Hypoglycemic Agents; D007328:Insulin; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D001640:Bicuculline