Opposite Effects of PSD-95 and MPP3 PDZ Proteins on Serotonin 5-Hydroxytryptamine2CReceptor Desensitization and Membrane Stability

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Abstract
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)2Creceptor. 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-HT2Creceptor-mediated Ca2+response, whereas MPP3 prevented desensitization of the Ca2+response. The effects of the PDZ proteins on the desensitization of the Ca2+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-HT2Creceptor response in neurons, by using a peptidyl mimetic of the 5-HT2Creceptor C terminus fused to the human immunodeficiency virus type-1 Tat protein transduction domain, which disrupts interaction between the 5-HT2Creceptor and PDZ proteins. Transduction of this peptide inhibitor into cultured cortical neurons increased the desensitization of the 5-HT2Creceptor-mediated Ca2+response. This indicates that, overall, interaction of 5-HT2Creceptors with PDZ proteins inhibits receptor desensitization in cortical neurons.