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INSULIN ENHANCEMENT OF HUMAN GLYCINE RECEPTOR IS SUBUNIT INDEPENDENT

¹ Depts. of Physiology,
² Pharmacology and
³ Anesthesia, University of Toronto, Toronto, Ontario;
⁴ Dept. of Anesthesia, Sunnybrook & Women's College HSC, Toronto, Ontario

INTRODUCTION

Insulin and glycine receptors (GlyRs) are involved in nociceptive processes including allodynia and hyperalgesia^1,23,4,5,6. We previously reported that insulin potentiates GlyRs in murine spinal neurons⁷ and speculated that this action contributes to antinociceptive properties of insulin that are independent of blood glucose levels. Adult GlyRs that mediate fast inhibitory transmission in the spinal cord are composed of ₁ and ß subunits. Here, we investigated the influence of subunit composition on the insulin sensitivity of human GlyRs.

METHODS

Experiments were undertaken in accordance with institutional animal care guidelines. Human embryonic kidney cells were transfected with human ₁ or ß GlyR cDNAs. Strychnine-sensitive whole cell currents evoked by glycine (100 µM, EC50) were recorded before and after the application of insulin (1 µM). Student's paired t-test determined statistical differences (p < 0.05).

RESULTS

Insulin increased the peak amplitude of currents recorded from homomeric a1 receptors from 2.06 ± 0.37 to 2.41 ± 0.44 nA, 18%, p < 0.05 and heteromeric ₁/ß receptors from 1.77 ± 0.31 to 2.12 ± 0.36 nA, 20%, p < 0.05. Thus, enhancement of GlyR function by insulin does not depend on the presence of the ß subunit. The potentiation of recombinant GlyR current was less than that observed for endogenous GlyRs present in murine spinal cord neurons (51%)⁷.

DISCUSSION

Insulin activates a receptor tyrosine kinase and thereby regulates a variety of ligand-gated channels. However, homomeric ₁ GlyRs lack putative consensus sites for tyrosine phosphorylation and are insensitive to factors that modulate tyrosine phosphorylation⁸. Therefore our findings indicate that insulin potentiates GlyR function through mechanisms that are independent of intracellular tyrosine kinase signaling cascades.

Acknowledgments

This work was supported by the First IARS Frontiers in Anesthesia Research Award and the CIHR to B.A.O. and J.F.M.

REFERENCES

1 Life Sci37:875;

2 Pharmacol Biochem Behav 29:73;

3 Pain 54:79;

4 Neurochem Res 21:1221;

5 Neuroreport 7:1922;

6 J Pharmacol Exp Ther 281:315;

7 Anesth Analg 2001 Abst in press;

8 Anesth Analg 2001 Abst in press.

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