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J Biol Chem, Vol. 273, Issue 33, 21416-21422, August 14, 1998

The Cytoplasmic Tail of the Human Somatostatin Receptor Type 5 Is Crucial for Interaction with Adenylyl Cyclase and in Mediating Desensitization and Internalization

From the Fraser Laboratories, Departments of Medicine, Neurology, and Neurosurgery and Pharmacology and Therapeutics, McGill University, Royal Victoria Hospital and the Montreal Neurological Institute, Montreal, Quebec H3A 1A1, Canada

We have investigated the role of the cytoplasmic tail (C-tail) of the human somatostatin receptor type 5 (hSSTR5) in regulating receptor coupling to adenylyl cyclase (AC) and in mediating agonist-dependent desensitization and internalization responses. Mutant receptors with progressive C-tail truncation (347, 338, 328, 318), Cys³²⁰  Ala substitution (to block palmitoylation), or Tyr³⁰⁴  Ala substitution of a putative NPXXY internalization motif were stably expressed in Chinese hamster ovary K1 cells. Except for the Tyr³⁰⁴  Ala mutant, which showed no binding, all other mutant receptors exhibited binding characteristics (K_d and B_max) and G protein coupling comparable with wild type (wt) hSSTR5. The C-tail truncation mutants displayed progressive reduction in coupling to AC, with the 318 mutant showing complete loss of effector coupling. Agonist pretreatment of wt hSSTR5 led to uncoupling of AC inhibition, whereas the desensitization response of the C-tail deletion mutants was variably impaired. Compared with internalization (66% at 60 min) of wt hSSTR5, truncation of the C-tail to 318, 328, and 338 residues reduced receptor internalization to 46, 46, and 23%, respectively, whereas truncation to 347 residues slightly improved internalization (72%). Mutation of Cys³²⁰  Ala induced a reduction in AC coupling, desensitization, and internalization. These studies show that the C-tail of hSSTR5 serves a multifunctional role in mediating effector coupling, desensitization, and internalization. Whereas coupling to AC is dependent on the length of the C-tail, desensitization and internalization require specific structural domains. Furthermore, internalization is regulated through both positive and negative molecular signals in the C-tail and can be dissociated from the signaling and acute desensitization responses of the receptor.

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