Somatostatin receptors present knowledge and future directions

Genes for five somatostatin receptor subtypes, designated sst1-5, have been cloned and shown to belong to the seven transmembrane domain receptor fami ly. The sst2 mRNA transcript is alternatively spliced to generate two relat ed receptor products (sst2A and sst2B) which differ in their carboxyl-termi nal sequence whereas each of the other genes is transcribed to give a singl e unique receptor protein. The six sst receptor subtypes all bind SRIF14, S RIF28 and the cortistatins with high affinity but vary in their affinity fo r analogs, such as octreotide. Although the tissue distribution of sst mRNA s has been extensively examined, much less is known about the cellular dist ribution of the individual receptor proteins. Recent studies with sst subty pe specific antibodies have localized individual sst receptors to specific cell types within the rat gastrointestinal tract, pancreas, pituitary and b rain. Furthermore, sst receptors have recently been identified in human tum ors by immunocytochemistry, providing a significantly improved method for s st receptor detection. All six sst receptor subtypes are linked to guanine nucleotide binding proteins (G proteins) and lead to inhibition of adenylyl cyclase following hormone binding. The sst receptors also regulate a varie ty of different effectors via G proteins, including calcium and potassium c hannels and serine and tyrosine phosphatases. In addition to signalling, tw o other processes are activated by hormone binding: receptor desensitizatio n and receptor internalization. The extent to which these occur seems to va ry for the different receptor subtypes. Recent studies have shown that the sst2A receptor is rapidly phosphorylated upon hormone binding, suggesting t hat this phosphorylation may be responsible for the desensitization and/or internalization of this receptor. The importance of receptor regulation in cellular responsiveness to somatostatin and for receptor detection as well as the molecular mechanisms by which these processes occur provide importan t areas for future investigations.