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First published online 5 October 2004
doi: 10.1242/jcs.01379

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New sorting nexin (SNX27) and NHERF specifically interact with the 5-HT_4(a) receptor splice variant: roles in receptor targeting

¹ Laboratoire de Génomique Fonctionnelle, CNRS UPR2580, CCIPE, 141 rue de la Cardonille, 34094 Montpellier CEDEX 05, France
² Institute of Molecular and Cell Biology, 30 Medical Drive, Singapore 117609, Rep. of Singapore

^* Author for correspondence (e-mail: joel.bockaert{at}ccipe.cnrs.fr)

Accepted 24 June 2004

The 5-hydroxytryptamine type 4 receptor (5-HT₄R) is involved in learning, feeding, respiratory control and gastrointestinal transit. This receptor is one of the G-protein-coupled receptors for which alternative mRNA splicing generates the most variants that differ in their C-terminal extremities. Some 5-HT₄R variants (a, e and f) express canonical PDZ ligands at their C-termini. Here, we have examined whether some mouse 5-HT₄R variants associate with specific sets of proteins, using a proteomic approach based on peptide-affinity chromatography, two-dimensional electrophoresis and mass spectrometry. We have identified ten proteins that interact specifically with the 5-HT_4(a)R and three that only associate with the 5-HT_4(e)R. Most of them are PDZ proteins. Among the proteins that associated specifically with the 5-HT_4(a)R variant, NHERF greatly modified its subcellular localization. Moreover, NHERF recruited the 5-HT_4(a)R to microvilli, where it localized with activated ezrin, consistent with the role of 5-HT_4(a)R in cytoskeleton remodelling. The 5-HT_4(a)R also interacted with both the constitutive and inducible (upon methamphetamine treatment) forms of the recently cloned sorting nexin 27 (SNX27a and b, respectively). We found that SNX27a redirected part of 5-HT_4(a)R to early endosomes. The interaction of the 5-HT₄R splice variants with distinct sets of PDZ proteins might specify their cellular localization as well as their signal transduction properties.

Key words: 5-HT₄ Receptor splice variants, PDZ domains, Proteomics, NHERF, Sorting nexin

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