Molecular biology of somatostatin receptor subtypes☆

Abstract 

Somatostatin (SRIF) receptors (ssts) comprise a family of heptahelical membrane proteins encoded by five related genes that map to separate chromosomes and which, with the exception of sst₁, are intronless. The ssts_1–4 display weak selectivity for SRIF-14 binding, whereas sst₅ is SRIF-28—selective. Based on structural similarity and reactivity for octapeptide and hexapeptide sst analogs, ssts_2,3 and sst₅ belong to a similar sst subclass; ssts_1–4 react poorly with these analogs and belong to a separate subclass. All five ssts are functionally coupled to inhibition of adenylyl cyclase via pertussis toxin-sensitive guanosine triphosphate (GTP)-binding proteins. mRNA for ssts_1–5 is widely expressed in brain and peripheral organs and displays an overlapping but characteristic pattern that is subtype-selective and tissue- and species-specific. All pituitary cell subsets express sst₂ and sst₅, with sst₅ being more abundant. Individual pituitary cells coexpress multiple sst subtypes. The binding pocket for SRIF-14 ligand lies deep within the membrane in transmembrane domains (TMDs) 3 to 7. Except for extracellular loop 2, it does not involve the other exofacial structures. Human (h)sst₂A and hsst₅ undergo agonist-mediated desensitization, associated with receptor internalization. The C-tail segment of hsst₅ displays positive molecular internalization signals. The ssts inhibit the growth of tumor cells directly, through blockade of mitogenic signaling leading to growth arrest and through induction of apoptosis. This process is associated with translocation of phosphotyrosine phosphatase (PTP) 1C from the cytosol to the membrane.

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