MOLECULAR-CLONING, FUNCTIONAL EXPRESSION AND PHARMACOLOGICAL CHARACTERIZATION OF THE HUMAN METABOTROPIC GLUTAMATE-RECEPTOR TYPE-4

A cDNA encoding the human metabotropic glutamate receptor type 4 (hmGl uR4) was isolated from human brain cDNA libraries by cross-hybridizati on with rat mGluR4 probes. The deduced amino acid sequence of human mG luR4 consists of 912 residues and shows a sequence identity of 96% to the amino acid sequence of rat mGluR4. Northern blot analyses indicate that hmGluR4 is strongly expressed in the cerebellum of the adult hum an brain but also at low levels in hippocampus, hypothalamus and thala mus. Stimulation of hmGluR4 with L-2-amino-4-phosphonobutyrate (L-AP4) , L-serine-O-phosphate (L-SOP), L-glutamate or (1S,3R)-1-aminocyclo-pe ntane-1,3-dicarboxylic acid ((1S,3R)-ACPD) in stably transfected Chine se hamster ovary (CHO) cells depressed forskolin-induced cAMP accumula tion, whereas quisqualate (0.5 mM) was ineffective. The rank order of agonist potencies is: L-AP4 > L-SOP > L-glutamate > (1S,3R)ACPD > > qu isqualate. (R,S)-alpha-methyl-4-carboxyphenylglycine (1 mM), a reporte d antagonist at some mGluR subtypes, did not reduce the depression of forskolin-induced cAMP accumulation by L-AP4.