Pancreastatin, a chromogranin A-derived peptide, activates G alpha(16) andphospholipase C-beta(2) by interacting with specific receptors in rat heart membranes

Pancreastatin (PST) is one of the chromogranin A (CGA)-derived peptides wit h known biological activity. It has a general inhibitory effect on secretio n in many exocrine and endocrine systems including the heart atrium. Beside s, a role of PST as a counter-regulatory peptide of insulin action has been proposed in the light of its effects on glucose and lipid metabolism in th e liver and adipose tissue, where receptors and signaling have been describ ed. G alpha (q/11) pathway seems to mediate PST action. Since PST has been shown to function as a typical calcium-dependent hormone, and increased pla sma levels have been found in essential hypertension correlating with catec holamines, we sought to study its possible interaction and signaling in hea rt membranes. Here, we are characterizing specific PST binding sites and si gnaling in rat heart membranes. We have found that PST receptor has a K-d O f 0.5 nM and a B-max of 34 fmol/mg of protein. The PST binding is inhibited by guanine nucleotides, suggesting the functional coupling of the receptor with GTP binding proteins (G proteins). Moreover, PST dose-dependently inc reases GTP binding to rat heart membranes. Finally, we have studied PST sig naling-effector system by measuring phospholipase C (PLC) activity using bl ocking antibodies against different G proteins and PLC isoforms. We have fo und that PST stimulates PLC>beta (2)>PLC beta (1)>PLC beta (3) by activatin g G(alpha 16) in rat heart membranes. These data suggest that PST may modul ate the cardiac function. (C) 2001 Elsevier Science Inc. All rights reserve d.