Rationale: The development of a refractory period for Ca2+ spark initiation after Ca2+ release in cardiac myocytes, should inhibit further Ca2+ release during the action potential (AP) plateau. However, Ca2+
release sites that did not initially activate, or which have prematurely recovered from refractoriness might release Ca2+ later during the AP and alter the cell-wide Ca2+ transient.
Objective: To investigate the possibility of late Ca2+ spark (LCS) activity in intact isolated cardiac myocytes using fast confocal line scanning with improved confocality and signal to noise.
Methods and Results: We recorded Ca2+ transients from cardiac ventricular myocytes isolated from rabbit hearts. APs were produced by electrical stimulation and rapid solution changes were used to modify the Ltype Ca2+ current. After the upstroke of the Ca2+ transient, late Ca2+ sparks (LCS) were detected which had increased amplitude compared to diastolic Ca2+ sparks. LCS are triggered by both L-type Ca2+ channel activity during the action potential plateau, as well as by the increase of cytosolic Ca2+ associated with the Ca2+ transient itself. Importantly, a mismatch between SR load and L-type Ca2+ trigger can increase the number of LCS. The likelihood of triggering a LCS also depends on recovery from refractoriness that appears after prior activation. Consequences of LCS include a reduced rate of decline of the Ca2+ transient and, if frequent, formation of microscopic propagating Ca2+ release events (Ca2+ ripples). Ca2+ ripples resemble Ca2+ waves in terms of local propagation velocity but spread for only a short distance due to limited regeneration.
Conclusions: These new types of Ca2+ signalling behaviour extend our understanding of Ca2+ mediated signalling. LCS may provide an arrhythmogenic substrate by slowing the Ca2+ transient decline as well as by amplifying maintained Ca2+ current effects on intracellular Ca2+ and consequently Na+/Ca2+ exchange current.
epub 24 December 2017
- Ca2+ sparks
- excitation-contraction coupling
- cytosolic Ca2+
- calcium signaling
- cardiac myocyte