Somatostatin Receptors

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Abstract
It is now well established that the biological actions of tetradecapeptide somatostatin (somatostatin-14, S-14) are receptor-mediated. These receptors were first quantified in GH4C pituitary tumor cells using [125I-Tyr1] S-14 as radioligand which was found to exhibit high non-specific binding to membrane receptor preparations from normal tissues. Our studies have shown that [125I-Tyr11] S-14 in which the radiolabel is situated away from the N-terminus exhibits significantly lower non-specific binding and therefore is more suitable for S-14 receptor studies. In the CNS, highest concentration of S-14 receptors was found in the cerebral cortex, followed by thalamus, hypothalamus, striatum, amygdala and hippocampus while medulla-pons, cerebellum and spinal cord exhibited negligible binding. Outside the CNS membrane receptors for S-14 have been characterized in pituitary, adrenal cortex and pancreatic acini. In all these tissues a single class of high affinity binding sites for S-14 were present, the receptors in pancreatic acinar cells exhibiting significantly greater affinity for binding S-14 than in other tissues. Structure-activity relationship studies using a number of structural analogs of S-14 have shown that the cyclic structure of the molecule is essential and that amino acid residues 7–11 (Phe-Trp-Lys-Phe-Phe) constitute the active recognition site for receptor binding. D-Trp8 modified analogs, in particular halogenated [D-Trp8] S-14 analogs, exhibited greater receptor binding affinity than S-14. The relative potencies of some of the analogs, e.g. [D-Trp8]S-14, [L-Br5-Trp8]S-14,[L-F5-Trp8]S-14 and [des AA1, 2, 4, 5, 12, 13, D-Trp8] S-14 were different between tissues suggesting that the S-14 receptors in these tissues are heterogeneous. Somatostatin-28 (S-28) bound to S-14 receptors in all the tissues but with significantly different affinities. Its affinity for binding to S-14 receptors was greater than that of S-14 in the pituitary but not in brain and exocrine pancreas whereas in the adrenal cortex both S-23 and S-14 exhibited comparable binding affinities. These data coupled with the observed greater biological potency of S-28 in some tissues suggest that separate receptors for S-28 distinct from those of S-14 may exist. Receptor sites quantitated with a radioligand prepared from a Tyr analog of S-28 — [Leu8, D-Trp22, 125I-Tyr25] S-28 — were found to exhibit binding parameters comparable to those quantitated with [125I-Tyr11]S-14 in each tissue. Furthermore, both S-28 and S-14 inhibited the receptor biding of these two radioligands with the same relative potencies. It appears, therefore, that both [125I-Tyr11] S-14 and [Leu8, D-Trp22, 125I-Tyr25] S-28 interact with the same receptor sites. In vivo radioautographic studies in the rat, however, indicate that [Leu8, D-Trp22, 125I-Tyr25] S-28 preferentially labels binding sites in median eminence which interact poorly with [125I-Tyr11] S-14. Thus the presence of distinct S-14 and S-28 receptors at least in discrete areas of rat brain appears likely. Further studies using more selective analogs of S-28 will be necessary to identify these receptors in direct binding studies. These receptors are regulated by changes in ligand concentration. Down-regulation of S-14 receptors following exposure to high concentrations of S-14 has been demonstrated in pituitary tumor cells GH4 C1 and AtT-20. Such homologous regulation of S-14 receptors in normal tissues may occur in pathophysiological conditions associated with elevated tissue and plasma somatostatin levels, but remains to be demonstrated by direct binding studies. Depletion of brain somatostatin by cysteamine was found to result in up-regulation of cerebrocortical S-14 receptors in the rat. Heterologous regulation of S-14 receptors by TRH and glucocorticoids has been reported in GH4C1 cells; such a regulation of S-14 in normal tissues has not been observed.