Palmitoylation of the 5-Hydroxytryptamine4a Receptor Regulates Receptor Phosphorylation, Desensitization, and

The mouse 5-hydroxytryptamine4a (5-HT4a) receptor is an un-usual member of the G protein-coupled receptor superfamily because it possesses two separate carboxyl-terminal palmi-toylation sites, which may allow the receptor to adopt different conformations in an agonist-dependent manner (J Biol Chem 277:2534–2546, 2002). By targeted mutation of the proximal (Cys-328/329) or distal (Cys-386) palmitoylation sites, or a combination of both, we generated 5-HT4a receptor variants with distinct functional characteristics. In this study, we showed that upon 5-HT stimulation, the 5-HT4a receptor undergoes rapid (t1/2 2 min) and dose-dependent (EC50 180 nM) phosphorylation on serine residues by a staurosporine-insen-sitive receptor kinase. Overexpression of GRK2 significantly reduced the receptor-promoted cAMP formation. The Cys328