Invited review: Significance of spatial and temporal heterogeneity of calcium transients in smooth muscle

The multiplicity of mechanisms involved in regulation of intracellular Ca²⁺ concentration ([Ca²⁺]_i) in smooth muscle results in both intra- and intercellular heterogeneities in [Ca²⁺]_i. Heterogeneity in [Ca²⁺]_i regulation is reflected by the presence of spontaneous, localized [Ca²⁺]_i transients (Ca²⁺ sparks) representing Ca²⁺ release through ryanodine receptor (RyR) channels. Ca²⁺ sparks display variable spatial Ca²⁺ distributions with every occurrence within and across cellular regions. Individual sparks are often grouped, and fusion of sparks produces large local elevations in [Ca²⁺]_i that occasionally trigger propagating [Ca²⁺]_i waves. Ca²⁺ sparks may modulate membrane potential and thus smooth muscle contractility. Sparks may also be the target of other regulatory factors in smooth muscle. Agonists induce propagating [Ca²⁺]_i oscillations that originate from foci with high spark incidence and also represent Ca²⁺ release through RyR channels. With increasing agonist concentration, the peak of regional [Ca²⁺]_i oscillations remains relatively constant, whereas both frequency and propagation velocity increase. In contrast, the global cellular response appears as a concentration-dependent increase in peak as well as mean cellular [Ca²⁺]_i, representing a spatial and temporal integration of the oscillations. The significance of agonist-induced [Ca²⁺]_i oscillations lies in the establishment of a global [Ca²⁺]_i level for slower Ca²⁺ -dependent physiological processes.