Characterization of cloned human somatostatin receptor SSTR5.

The recent molecular cloning of the genes encoding six distinct somatostatin (SRIF) receptor subtypes from various species has allowed for the individual expression and characterization of these receptors in mammalian cells. In the present study, we have cloned the human homologue of the SRIF receptor subtype SSTR5 (formerly termed SSTR4) and characterized its pharmacological and functional properties, as well as its distribution. Although there is 80.5% sequence homology between the cloned rat and human SSTR5 receptors, their pharmacological profiles differ. We have labeled both rat and human SSTR5, expressed in Chinese hamster ovary (CHO-K1) cells, with 125I-Tyr11-SRIF and performed inhibition studies using SRIF analogues of differing structures, including cyclic penta-, hexa-, and octapeptide SRIF analogues. Whereas rat SSTR5 bound compounds in all structural classes with high to moderate affinities, human SSTR5 bound most SRIF analogues with much lower affinity, with the exceptions of SRIF, SRIF-28, and L-362,855. Like rat SSTR5, human SSTR5 mediated the inhibition by SRIF of forskolin-stimulated cAMP accumulation. However, the clinically used SRIF analogue SMS 201-995, which potently inhibited cAMP formation via interaction with rat SSTR5, did not inhibit cAMP accumulation in cells expressing human SSTR5. The distribution of expression of human SSTR5 mRNA, as analyzed by reverse transcription-polymerase chain reaction, shows selective expression in small intestine, heart, adrenal, cerebellum, pituitary, placenta, and skeletal muscle but not in kidney, liver, pancreas, uterus, thymus, testis, spleen, lung, thyroid, ovary, or mammary gland. The structural differences between cloned rat and human SSTR5 receptors suggest useful strategies for identifying regions of this receptor subtype that may be involved in ligand binding specificities. Identification of subtype-selective SRIF analogues may lead to more specific pharmacological therapeutic interventions.