6agonist selectivity determinants in somatostatin receptor subtypes I and II.

The biological activities of the peptide hormone somatostatin are mediated through a recently identified family of G-protein-linked receptors.A number of somatostatin analogs have been characterized with selective affinities for particular somatostatin receptor subtypes.Using one such molecule (MK-6781, we have delineated receptor regions that determine analog selectivity in the murine Type 1 and Type 2 somatostatin receptors.We find that the regions about the second and third extracellular loops of these two receptors contain the determinants for MK-678 selectivity and affinity.Somatostatin (SR1F)I is a cyclic peptide hormone shown to inhibit the secretion of a number of pancreatic, pituitary, and gastrointestinal hormones (for reviews, see Refs. 1 and 2).SRIF is also present in the central nervous system where it is believed to modulate a myriad of processes, including nociception, cognition, and locomotor activity (3-6).SRIF-responsive cells exhibit hormone-dependent inhibition of CAMP production, stimulation of tyrosine phosphatase activity (71, and ion channel regulation.There are currently five mammalian SRIF receptor (SRIF-R) genes identified (8-11), with sequence similarities ranging from 41 to 60% between any given pair of receptors.Sequence analysis reveals seven putative transmembrane regions in all SRIF-Rs, placing these proteins in the receptor superfamily associated with G-protein-dependent signal transduction pathways.The opioid receptors have the highest sequence similarity to the SRIF-Rs (3240%) (12-X), followed by the chemokine receptors, as exemplified by the interleukin-8 and macrophage inflammatory protein-la receptors (23-31% similarity) (16-18).The existence of multiple SRIF-R subtypes with clearly different (though sometimes overlapping) expression patterns (8, 19-21) suggests subtype-specific SRIF-R activities.The characterization of such activities is an ongoing process closely tied to the development of subtype-specific SRIF analogs (22)(23)(24).At the present, no SRIF analogs have been characterized that are truly monospecific.Nevertheless, a significant number of SRIF-R agonists have been identified with markedly different affinities for different SRIF-R subtypes.The use of such analogs in functional assays has indicated involvement of a Type 2 * The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.