Insulin increases the potency of glycine at ionotropic glycine receptors.
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 microM) also shifted the glycine concentration-response plot to the left and reduced the glycine EC(50) value from 52 to 31 microM. Currents evoked by a submaximal concentration of glycine were increased to approximately 140% of control. The glycine receptor alpha subunit was sufficient for the enhancement by insulin because currents from recombinant homomeric alpha(1) receptors and heteromeric alpha(1)beta receptors were both increased. Insulin acted at the insulin receptor via pathways dependent on tyrosine kinase and phosphatidylinositol 3 kinase because 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.
Caraiscos
Valerie B
VB
Institute of Medical Science, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
Bonin
Robert P
RP
Newell
J Glen
JG
Czerwinska
Elzbieta
E
Macdonald
John F
JF
Orser
Beverley A
BA
D000818:Animals; D002478:Cells, Cultured; D004357:Drug Synergism; D005998:Glycine / Q000378:metabolism*; D006096:Gramicidin / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D018009:Receptors, Glycine / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D015032:Zinc / Q000378:metabolism
D007328:Insulin; D021122:Protein Subunits; D018009:Receptors, Glycine; D006096:Gramicidin; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D015032:Zinc; D005998:Glycine