Agonist-independent activation of metabotropic glutamate receptors by the intracellular protein Homer.
G-protein-coupled receptors (GPCRs) transduce signals from extracellular transmitters to the inside of the cell by activating G proteins. Mutation and overexpression of these receptors have revealed that they can reach their active state even in the absence of agonist, as a result of a natural shift in the equilibrium between their inactive and active conformations. Such agonist-independent (constitutive) activity has been observed for the glutamate GPCRs (the metabotropic glutamate receptors mGluR1a and mGluR5) when they are overexpressed in heterologous cells. Here we show that in neurons, the constitutive activity of these receptors is controlled by Homer proteins, which bind directly to the receptors' carboxy-terminal intracellular domains. Disruption of this interaction by mutagenesis or antisense strategies, or expression of endogenous Homer1a (H1a), induces constitutive activity in mGluR1a or mGluR5. Our results show that these glutamate GPCRs can be directly activated by intracellular proteins as well as by agonists.
Ango
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F
CNRS-UPR 9023, CCIPE, 141 Rue de la Cardonille, 34000 Montpellier, France.
Prézeau
L
L
Muller
T
T
Tu
J C
JC
Xiao
B
B
Worley
P F
PF
Pin
J P
JP
Bockaert
J
J
Fagni
L
L
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D000072233:Homer Scaffolding Proteins; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D016372:RNA, Antisense / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins
D002352:Carrier Proteins; C578936:Grm5 protein, mouse; D000072233:Homer Scaffolding Proteins; D009479:Neuropeptides; D016372:RNA, Antisense; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D011994:Recombinant Proteins; C104077:metabotropic glutamate receptor type 1