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Cloning and expression of a human metabotropic glutamate receptor 1 alpha: enhanced coupling on co-transfection with a glutamate transporter.

Desai M.A., Burnett J.P., Mayne N.G., Schoepp D.D.

We cloned and expressed a human metabotropic glutamate receptor 1 alpha (HmGluR1 alpha) in a novel cell line. The human mGluR1 alpha cDNA was found to be 86% identical to rat mGluR1 alpha, and the predicted protein sequence was found to be 93% identical to rat mGluR1 alpha. We expressed HmGluR1 alpha in AV12-664, an adenovirus-transformed Syrian hamster cell line. To prevent tonic activation of HmGluR1 alpha by glutamate that may be released by these cells into the extracellular medium, HmGluR1 alpha was co-expressed in AV12-664 cells with a rat glutamate/aspartate transporter (GLAST). This allowed investigation of the effect that clearance of glutamate from the extracellular space would have on HmGluR1 alpha function. A comparison of mRNA levels revealed that HmGluR1 alpha was similarly expressed in cells with or without co-expression of GLAST. However, HmGluR1 alpha-mediated phosphoinositide hydrolysis was efficiently elicited only in cells co-expressing rat GLAST. Blockade of glutamate transport by L-trans-pyrrolidine-2,4-dicarboxylic acid resulted in an increase in glutamate levels in the media and an increase in basal HmGluR1 alpha-mediated phosphoinositide hydrolysis. Long-term pretreatment of cells with L-trans-pyrrolidine-2,4-dicarboxylic acid resulted in media glutamate levels similar to those in cells not expressing GLAST. However, this resulted in a dramatic decrease in 1-aminocyclopentane-1S,3R-dicarboxylic acid- and glutamate-stimulated phosphoinositide hydrolysis. These studies suggest that co-expression of mGluR1 alpha with a glutamate transporter prevents desensitization of the receptor, thus achieving optimal coupling of the receptor with its effector system.

Mol. Pharmacol. 48:648-657(1995) [PubMed] [Europe PMC]

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