Somatostatin receptor subtype 1 (sst(1)) regulates intracellular 3',5'-cyclic adenosine monophosphate accumulation in rat embryonic cortical neurons: evidence with L-797,591, an sst(1)-subtype-selective nonpeptidyl agonist

Somatostatin (SRIF) initiates its biological activities by interacting with five homologous G-protein-coupled receptor subtypes (sst(1--5)). In the mammalian nervous system, sst(1--5) receptor mRNA expression patterns have been localized by in situ hybridization studies, or at the protein level with receptor-specific antibodies. Cortical responses to SRIF have been demonstrated, although a functional relationship between an SRIF effect and an individual receptor subtype is lacking. The recent development of novel, subtype-selective SRIF receptor ligands now provides a means to correlate receptor subtype expression patterns with the corresponding biological function. In cultured monolayers of E17-18 rat embryonic cortical neurons, 10(-7) M SRIF-28 inhibited 10(-6) M forskolin-stimulated cAMP accumulation by 37%, a level of inhibition that was mimicked by L-797,591, a potent sst(1)-selective agonist. SRIF-14 or L-797,591 inhibited forskolin-stimulated cAMP accumulation in a concentration-dependent fashion, with EC(50)s (effective concentration for 50% maximal response) of 8.0 x 10(-10) M and 7.0 x 10(-10) M, respectively. No similar concentration-dependent effect on forskolin-stimulated cAMP levels was observed with sst(2)-, sst(3)- or sst(4)-selective agonists. Furthermore, both SRIF-14 and L-797,591 inhibited 10(-7) M CRH-induced cAMP in the embryonic neurons. These results are the first evidence demonstrating that sst(1) regulates intracellular cAMP levels in embryonic neurons and may inhibit CRH-mediated effects in the embryonic cortex.