Somatostatin Receptor 5

Description

The cyclic tetradecapeptide somatostatin (SST; 182450) is widely distributed throughout the body and is an important regulator of endocrine and nervous system function. It exerts its biologic actions by binding to specific high-affinity receptors on the cell surface. Somatostatin receptors are a group of structurally related proteins that are members of the 7 transmembrane-spanning family of G protein-coupled receptors (summary by Yasuda et al., 1993).

Cloning and Expression

Yamada et al. (1993) cloned human somatostatin receptor-4 (SSTR4; 182454) and SSTR5 and determined their functional expression and pharmacologic characteristics. Moldovan et al. (1998) cloned the mouse Sstr5 cDNA.

Gene Function

Somatostatin and dopamine are 2 major neurotransmitter systems that share a number of structural and functional characteristics. Somatostatin receptors and dopamine receptors are colocalized in neuronal subgroups, and somatostatin is involved in modulating dopamine-mediated control of motor activity. Using photobleaching fluorescence resonance energy transfer (FRET), Rocheville et al. (2000) demonstrated that the receptors SSTR5 and D2R (126450) interact physically through heterooligomerization to create a novel receptor with enhanced functional activity. The neurotransmitter for either receptor promoted heterodimerization, but the presence of both ligands did not produce an additive or synergistic interaction (Milligan, 2000). The results of Rocheville et al. (2000) provided evidence that receptors from different G protein-coupled receptor families interact through oligomerization. Such direct intramembrane association defines a new and more complex level of molecular crosstalk between related G protein-coupled receptor subfamilies.

Zatelli et al. (2001) determined that the human medullary thyroid carcinoma cell line TT (characterized by the presence of a mutation involving exon 11 of RET, 164761.0012), expresses all SSTR subtypes; that SSTR2 (182452) activation inhibits DNA synthesis and cell proliferation, whereas SSTR5 activation increases DNA synthesis; and that an SSTR2 preferential agonist can antagonize SSTR5-selective agonist action, and vice versa. These findings suggest a tissue-specific function and a tissue-specific interaction between the 2 receptors.

Ardjomand et al. (2003) investigated the distribution of SSTR2, SSTR3 (182453), and SSTR5 in uveal melanomas and their diagnostic and possible therapeutic value. All 25 uveal melanomas studied were positive for SSTR2: SSTR2A was expressed in 15 of 25; SSTR2B in 23 of 25; SSTR3 in 7 of 25; and SSTR5 in 13 of 25. A Kaplan-Meier survival curve showed a significantly better ad vitam prognosis for patients with tumors expressing high levels of SSTR2. Because a melanoma cell proliferation assay showed an inhibitory effect of up to 36% +/- 6% using octreotide or vapreotide, somatostatin analogs might be beneficial in the treatment of patients with ocular melanomas.

Normal pancreatic beta cells express SSTRs. Bertherat et al. (2003) determined the prevalence of SSTR expression in vitro and characterized SSTR subtype binding in insulinomas and its correlation with in vivo SSTR scintigraphy. Semiquantitative RT-PCR of SSTR mRNA was performed for 20 insulinomas. SSTR2 and SSTR5 were expressed in 70%, SSTR1 (182451) in 50%, and SSTR3 and SSTR4 subtypes only in 15 to 20% of the tumors. Displacement experiments with ligands of higher affinity for each of the SSTRs revealed significant binding with the SSTR2 and SSTR5 ligands in 72%, SSTR3 in 44%, SSTR1 in 44%, and SSTR4 in 28% of cases. The authors concluded that loss of expression of SSTR2/SSTR5 in a third of insulinomas may be involved in beta-cell dysfunction.

Using an SSTR2-selective antagonist, Ren et al. (2003) showed that both SSTR2 and SSTR5 participate in the suppression of GH (139250) by somatostatin (182450) in the human fetal pituitary. The results demonstrated that either SSTR2 or STR5 may independently suppress GH secretion from the pituitary. Activation of both SSTR2 and SSTR5 induced a functional, synergistic association of the receptor subtypes that resulted in enhanced suppression of G secretion.

Palmitoylation of cysteine residues within intracellular C-terminal tails of G protein-coupled receptors creates an additional intracellular loop important for efficient coupling of the receptor to G proteins and is believed to target receptors to lipid rafts. Using rat Sstr5 as bait to screen a mouse brain expression library, and by immunoprecipitation analysis of transfected HEK293 cells, Kokkola et al. (2011) showed that Sstr5 interacted directly with the palmitoyl acyltransferase Zdhhc5 (614586). Deletion analysis revealed that the first 2 transmembrane domains of Zdhhc5 were required to interact with the Sstr5 C-terminal tail. Overexpression of Zdhhc5 increased palmitoylation of Sstr5, and small interfering RNA-mediated knockdown of ZDHHC5 inhibited Sstr5 palmitoylation.

Mapping

Takeda et al. (1995) mapped the SSTR5 gene to chromosome 16 on the basis of its segregation in a panel of reduced human/rodent somatic cell hybrid cell lines. Takeda et al. (1995) localized the SSTR5 gene to 16p13.3 by fluorescence in situ hybridization. By interspecific backcross analysis, Brinkmeier and Camper (1997) mapped the Sstr5 gene to mouse chromosome 17.

Evolution

Conservation

The 400-Mb genome of the Japanese pufferfish, Fugu rubripes, is relatively free of repetitive DNA and contains genes with small introns at high density. Sandford et al. (1996) demonstrated that the genes that are mutant in polycystic kidney disease-1 (PKD1; 601313) and tuberous sclerosis-2 (TSC2; 191092) are conserved in the Fugu genome where they are tightly linked. In addition, sequences homologous to the SSTR5 gene were identified 5-prime to PKD1, defining a larger syntenic region. As in genomes of mouse and human, the Fugu TSC2 and PKD1 genes are adjacent in a tail-to-tail orientation.

Molecular Genetics

Ballare et al. (2001) reported a mutation in the SSTR5 gene (182455.0001) that abrogated the antiproliferative action of somatostatin and activated mitogenic pathways in a patient with acromegaly (102200) resistant to somatostatin analog octreotide who also carried an activating GNAS (R201C; 139320.0008) mutation.