PT  - JOURNAL ARTICLE
AU  - Emmanuel Hermans
AU  - Ruth Saunders
AU  - Julie V. Selkirk
AU  - Rajendra Mistry
AU  - Stefan R. Nahorski
AU  - R. A. John Challiss
TI  - Complex Involvement of Pertussis Toxin-Sensitive G Proteins in the Regulation of Type 1α Metabotropic Glutamate Receptor Signaling in Baby Hamster Kidney Cells
AID  - 10.1124/mol.58.2.352
DP  - 2000 Aug 01
TA  - Molecular Pharmacology
PG  - 352--360
VI  - 58
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/58/2/352.short
4100  - http://molpharm.aspetjournals.org/content/58/2/352.full
SO  - Mol Pharmacol2000 Aug 01; 58
AB  - Previously, we demonstrated that the coupling of the metabotropic glutamate receptor mGlu1α to phosphoinositide hydrolysis is enhanced by pertussis toxin (PTX) in stably transfected baby hamster kidney cells (BHK). Here, we show that the PTX effect on agonist-stimulated [3H]inositol phosphate accumulation can be resolved into two components: an immediate increase in agonist potency, and a more slowly developing increase in the magnitude of the response observed at maximally effective agonist concentrations. Using Gq/11α- and Gi/oα-selective antibodies to immunoprecipitate [35S]guanosine-5′-O-(3-thio)triphosphate-bound Gα proteins, we also show that agonist stimulation of mGlu1α in BHK membranes increases specific [35S]guanosine-5′-O-(3-thio)triphosphate binding to both Gq/11 and Gi/o proteins. Preincubation of BHK-mGlu1α with l-glutamate (300 μM) results in a progressive loss (60% in 30 min) ofl-quisqualate-induced [3H]inositol phosphate accumulation (without a change in potency), providing evidence for agonist-induced receptor desensitization. Although such desensitization of mGlu receptor signaling was mimicked by a phorbol ester, agonist-induced phosphorylation of the receptor was not observed and protein kinase C inhibition by Ro 31-8220 did not preventl-glutamate-mediated desensitization. In contrast, PTX treatment of the cells almost completely preventedl-glutamate-mediated desensitization. Together, these data provide evidence for a multifunctional coupling of mGlu1α to different types of G proteins, including PTX-sensitive Gi-type G proteins. The latter are involved in the negative control of phospholipase C activity while also influencing the rate of desensitization of the mGlu1α receptor.