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Journal of Neuroscience, Vol 15, 3970-3981, Copyright © 1995 by Society for Neuroscience
Molecular, functional, and pharmacological characterization of the metabotropic glutamate receptor type 5 splice variants: comparison with mGluR1
C Joly, J Gomeza, I Brabet, K Curry, J Bockaert and JP Pin
Mecanismes Moleculaires des Communications Cellulaires UPR 9023, CNRS CCIPE, Montpellier, France.
The main excitatory neurotransmitter in the brain, glutamate (Glu),
activates not only receptor-channels, but also receptors coupled to G-
protein called metabotropic Glu receptors (mGluRs). Eight genes coding for
mGluRs have been characterized to date giving rise to even more proteins
due to alternative splicing phenomena. Here we characterized a splice
variant of mGluR5, called mGluR5b which contains a 32 amino acid fragment
inserted in the cytoplasmic tail, 50 residues after the 7th transmembrane
domain. mGluR5b mRNAs are present in different regions of the adult rat
brain and are expressed at a higher level than mGluR5a mRNA. Functional
analysis of mGluR5a and mGluR5b revealed that they share all the properties
of mGluR1a, but not those of mGluR1b or 1c. Like mGluR1a, both mGluR5a and
mGluR5b activate a rapid and transient current in Xenopus oocytes. When
expressed in LLC-PK1 cells, they show the same subcellular distribution as
mGluR1a, and stimulate both inositol phosphate (IP) and cAMP production.
Moreover, cells expressing mGluR5a or mGluR5b, like those expressing
mGluR1a have a higher basal PLC activity that is not inhibited by
glutamate-pyruvate transaminase (GPT), suggesting that these receptors have
an intrinsic activity. Interestingly, the pharmacological profiles of
mGluR5a and b are identical, but different from that of mGluR1a. Most
agonists, except glutamate, are more potent on mGluR5a/b than on mGluR1a.
Interestingly, the mGluR1a antagonists MCPG and 4CPG have no effect on
mGluR5a/b; 4C3HPG which is a full antagonist at mGluR1a is a partial
agonist at mGluR5a/b. These results indicate that the long C-terminal
intracellular domain present only in mGluR1a and mGluR5a/b, although not
well conserved, is likely to be involved in the specific functional
properties of these receptors. Although the ligand recognition sites of
mGluR5a/b and mGluR1a are highly conserved, these receptors have different
pharmacology.
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