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

Abstract

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 50s (effective concentration for 50% maximal response) of 8.0×10 −10 M and 7.0×10 −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.