Opposite effects of PSD-95 and MPP3 PDZ proteins on serotonin 5-hydroxytryptamine2C receptor desensitization and membrane stability.
PSD-95/Disc large/Zonula occludens 1 (PDZ) domain-containing proteins (PDZ proteins) play an important role in the targeting and the trafficking of transmembrane proteins. Our previous studies identified a set of PDZ proteins that interact with the C terminus of the serotonin 5-hydroxytryptamine (5-HT)(2C) receptor. Here, we show that the prototypic scaffolding protein postsynaptic density-95 (PSD-95) and another membrane-associated guanylate kinase, MAGUK p55 subfamily member 3 (MPP3), oppositely regulate desensitization of the receptor response in both heterologous cells and mice cortical neurons in primary culture. PSD-95 increased desensitization of the 5-HT(2C) receptor-mediated Ca(2+) response, whereas MPP3 prevented desensitization of the Ca(2+) response. The effects of the PDZ proteins on the desensitization of the Ca(2+) response were correlated with a differential regulation of cell surface expression of the receptor. Additional experiments were performed to assess how PDZ proteins globally modulate desensitization of the 5-HT(2C) receptor response in neurons, by using a peptidyl mimetic of the 5-HT(2C) receptor C terminus fused to the human immunodeficiency virus type-1 Tat protein transduction domain, which disrupts interaction between the 5-HT(2C) receptor and PDZ proteins. Transduction of this peptide inhibitor into cultured cortical neurons increased the desensitization of the 5-HT(2C) receptor-mediated Ca(2+) response. This indicates that, overall, interaction of 5-HT(2C) receptors with PDZ proteins inhibits receptor desensitization in cortical neurons.
Gavarini
Sophie
S
Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, Institut National de la Santé et de la Recherche Médicale, U661, Université Montpellier I, Université Montpellier II, Montpellier Cedex 5, France.
Bécamel
Carine
C
Altier
Christophe
C
Lory
Philippe
P
Poncet
Joël
J
Wijnholds
Jan
J
Bockaert
Joël
J
Marin
Philippe
P
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002522:Chlorocebus aethiops; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000166:cytology; D009479:Neuropeptides / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D014981:Xenopus
D048868:Adaptor Proteins, Signal Transducing; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009479:Neuropeptides; D044405:Receptor, Serotonin, 5-HT2C; D010768:Phosphoserine; C491075:Dlgh3 protein, mouse; D051528:Guanylate Kinases; D002118:Calcium