The modulating effect on L-type Ca2+ channels of a small molecular weight material isolated from rat brain, called endogenous modulator, was studied in guinea pig and rat ventricular myocytes, and rabbit portal vein myocytes. In nonphosphorylated L-type channels of cardiac and portal vein myocytes the endogenous modulator increased Ca2+ current by 2 to 4 fold. This effect was attenuated by increasing the intracellular cAMP content and in 53% of the cells led to a suppressive effect on Ca2+ current. Extracellularly, but not intracellularly applied 12,13-phorbol- doacetate blocked the increase in Ca2+ current elicited by the endogenous modulator. Ascorbic acid or glucaric acid, which have a similar molecular weight, failed to mimic the enhancing effect of the endogenous modulator. We conclude that the endogenous modulator has two independent actions on L-type Ca2+ channel: (1) An antagonistic effect that occurs rapidly and may be related to its nitrendipine-displacing effect; and (2) An agonistic effect that could be mediated through a novel signalling pathway involving a phorbol-like receptor.
