Functional, electrophysiological and molecular docking analysis of the modulation of Ca v 1.2 channels in rat vascular myocytes by murrayafoline A

Background and Purpose The carbazole alkaloid murrayafoline A (MuA) enhances contractility and the Ca 2+ currents carried by the Ca v 1.2 channels [I Ca1.2 ] of rat cardiomyocytes. As only few drugs stimulate I Ca1.2 , this study was designed to analyse the effects of MuA on vascular Ca v 1.2 channels. Experimental Approach Vascular activity was assessed on rat aorta rings mounted in organ baths. Ca v 1.2 Ba 2+ current [I Ba1.2 ] was recorded in single rat aorta and tail artery myocytes by the patch‐clamp technique. Docking at a 3D model of the rat, α 1c central pore subunit of the Ca v 1.2 channel was simulated in silico . Key Results In rat aorta rings MuA, at concentrations ≤14.2 μM, increased 30 mM K + ‐induced tone and shifted the concentration‐response curve to K + to the left. Conversely, at concentrations >14.2 μM, it relaxed high K + depolarized rings and antagonized Bay K 8644‐induced contraction. In single myocytes, MuA stimulated I Ba1.2 in a concentration‐dependent, bell‐shaped manner; stimulation was stable, incompletely reversible upon drug washout and accompanied by a leftward shift of the voltage‐dependent activation curve. MuA docked at the α 1C subunit central pore differently from nifedipine and Bay K 8644, although apparently interacting with the same amino acids of the pocket. Neither Bay K 8644‐induced stimulation nor nifedipine‐induced block of I Ba1.2 was modified by MuA. Conclusions and Implications Murrayafoline A is a naturally occurring vasoactive agent able to modulate Ca v 1.2 channels and dock at the α 1C subunit central pore in a manner that differed from that of dihydropyridines. © 2015 The British Pharmacological Society