MOLECULAR PHARMACOLOGY OF SOMATOSTATIN RECEPTORS

Somatostatin was discovered for its ability to inhibit growth hormone (GH) secretion. Later, it was found to be widely distributed in other brain regions, in which it fulfills a neuromodulatory role, and in sev eral organs of the gastrointestinal tract where it can act as a paracr ine factor or as a true circulating factor. In mammals, two molecules of 14 (somatostatin 14) and 28 (somatostatin 28) amino acids are the o nly biologically active members of the family. They originate from a s ingle gene which gives rise to a single propeptide alternately cleaved in different tissues. In 1992, a major breaktrough in our understandi ng of somatostatin functions was made with the cloning of five differe nt receptor genes (sstr1 to sstr5) which belong to the seven transmemb rane domain receptor family. Their closer relatives are opioid recepto rs. In first approximation, the tissular expression of the sstrs match es quite well with the distribution of somatostatin binding sites in t he ''classical'' targets of the peptide ie brain, pituitary pancreatic islets and adrenals. The pharmacology of GH inhibition is very close to sstr2 binding but other actions of somatostatins have not yet been attributed clearly to a single receptor subtype. All clinically releva nt agonists tested so far (octreotide, lanreotide and vapreotide) are selective of sstr2 being less potent on sstr3 and inactive for sstr1 a nd sstr4. Surprisingly, rat sstr5 displays nanomolar affinities for oc treotide and vapreotide while these agonists are only active at much h igher concentrations on human sstr5. Ah five receptors can be more or less efficiently coupled to inhibition of adenylate cyclase activity i n transfected cell systems. However, the transduction of somatostatin antisecretory and antiproliferative actions through multiple intracell ular effecters and their relation to the diversity of the receptors re main to be established as yet.