Store-operated Ca2+ entry and depolarization explain the anomalous behaviour of myometrial SR: Effects of SERCA inhibition on electrical activity, Ca2+ and force

Abstract

In the myometrium SR Ca2+ depletion promotes an increase in force but unlike several other smooth muscles, there is no Ca2+ sparks-STOCs coupling mechanism to explain this. Given the importance of the control of contractility for successful parturition, we have examined, in pregnant rat myometrium, the effects of SR Ca2+-ATPase (SERCA) inhibition on the temporal relationship between action potentials, Ca2+ transients and force. Simultaneous recording of electrical activity, calcium and force showed that SERCA inhibition, by cyclopiazonic acid (CPA 20μM), caused time-dependent changes in excitability, most noticeably depolarization and elevations of baseline [Ca2+]i and force. At the onset of these changes there was a prolongation of the bursts of action potentials and a corresponding series of Ca2+ spikes, which increased the amplitude and duration of contractions. As the rise of baseline Ca2+ and depolarization continued a point was reached when electrical and Ca2+ spikes and phasic contractions ceased, and a maintained, tonic force and Ca2+ was produced. Lanthanum, a non-selective blocker of store-operated Ca2+ entry, but not the L-type Ca2+ channel blocker nifedipine (1–10μM), could abolish the maintained force and calcium. Application of the agonist, carbachol, produced similar effects to CPA, i.e. depolarization, elevation of force and calcium. A brief, high concentration of carbachol, to cause SR Ca2+ depletion without eliciting receptor-operated channel opening, also produced these results. The data obtained suggest that in pregnant rats SR Ca2+ release is coupled to marked Ca2+ entry, via store operated Ca2+ channels, leading to depolarization and enhanced electrical and mechanical activity.