Calcium channel activity and force regulation in smooth muscle: Effects of polyamines and growth stimulation

Sammanfattning: The initial signal for contraction in smooth muscle is an increase in [Ca2+]i. Ca2+ ions can either enter the cytosol from the extracellular medium or be released from intracellular stores. Voltage-operated Ca2+ channels (VOC) play a dominant role in the activation of smooth muscle contraction. This thesis describes two novel regulatory mechanisms of the dihydropyridine (DHP)-sensitive VOC in smooth muscle. One of them involves the polyamines spermine (SP) and spermidine (SPD), and the other, a Ca2+-dependent modulation brought about by growth stimulation with foetal calf serum (FCS). The polyamines SP and SPD, ubiquitous polycations associated with cell growth and differentiation, inhibited electrical membrane activity and contraction in intestinal and vascular smooth muscle. We showed in guinea-pig ileum that this was due to inhibition of current through L-type Ca2+ channels. SP and SPD also increased Ca2+ sensitivity of the contractile system. Culture with the adenosylmethionine decarboxylase antagonist CGP 48664 reduces SP and SPD contents by more than 50 % and causes enhanced Ca2+ channel activity. This is consistent with increased spontaneous activity observed after culture with CGP 48664. Culture of intestinal smooth muscle with FCS reduced sensitivity of force to extracellular Ca2+ by a functional decrease in Ca2+ channel density. Downregulation of inward current was mediated by an increased [Ca2+]i, since it was reversed by the Ca2+ channel blocker verapamil and mimicked by the Ca2+ ionophore ionomycin. We conclude that the increased [Ca2+]i brought about by culture with FCS gives rise to a persistent and trophic modulation of L-type Ca2+ channel, in contrast to the direct modulation exerted by altered endogenous polyamines.