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-HT4(a)R and three that only 
associate with the 5-HT4(e)R. Most of them are PDZ proteins. Among the proteins 
that associated specifically with the 5-HT4(a)R variant, NHERF greatly modified 
its subcellular localization. Moreover, NHERF recruited the 5-HT4(a)R to 
microvilli, where it localized with activated ezrin, consistent with the role of 
5-HT4(a)R in cytoskeleton remodelling. The 5-HT4(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-HT4(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.