Received for publication December 27, 2006.
Revised February 9, 2007.
Accepted for publication February 15, 2007.

Insulin increases the potency of glycine at ionotropic glycine receptors

Abstract

The mechanisms by which insulin modulates neuronal plasticity and pain processes remain poorly understood. Here we report that insulin rapidly increases the function of glycine receptors in murine spinal neurons and recombinant human glycine receptors expressed in human embryonic kidney cells. Whole-cell patch clamp recordings showed that insulin reversibly enhanced current evoked by exogenous glycine and increased the amplitude of spontaneous glycinergic miniature inhibitory postsynaptic currents recorded in cultured spinal neurons. Insulin (1 µM) also shifted the glycine concentration-response plot to the left and reduced the glycine EC₅₀ value from 52 µM to 31 µM. Currents evoked by a submaximal concentration of glycine were increased to approximately 140% of control. The glycine receptor subunit was sufficient for the enhancement by insulin as currents from recombinant homomeric ₁ receptors and heteromeric ₁ receptors were both increased. Insulin acted at the insulin receptor via pathways dependent on tyrosine kinase and phosphatidylinositol 3 kinase as the insulin effect was eliminated by the insulin receptor antagonist, hydroxy-2-naphthalenylmethylphosphonic acid trisacetoxymethyl ester, the tyrosine kinase inhibitor lavendustin A, and the phosphatidylinositol 3 kinase antagonist wortmannin. Together, these results show that insulin has a novel regulatory action on the potency of glycine for ionotropic glycine receptors.

Key words: Glycine, Ion channel regulation, Insulin, Src and other nonreceptor tyrosine kinases