‘Ca2+-induced Ca2+ entry’ or how the L-type Ca2+ channel remodels its own signalling pathway in cardiac cells

The adjustment of Ca2+ entry in cardiac cells is critical to the generation of the force necessary for the myocardium to meet the physiological needs of the body. In this review, we present the concept that Ca2+ can promote its own entry through Ca2+ channels by different mechanisms. We refer to it under the general term of ‘Ca2+-induced Ca2+ entry’ (CICE). We review short-term mechanisms (usually termed facilitation) that involve a stimulating effect of Ca2+ on the L-type Ca2+ current (ICa-L) amplitude (positive staircase) or a lessening of Ca2+-dependent inactivation of ICa-L. This latter effect is related to the amount of Ca2+ released by ryanodine receptors (RyR2) of the sarcoplasmic reticulum (SR). Both effects are involved in the control of action potential (AP) duration. We also describe a long-term mechanism based on Ca2+-dependent down-regulation of the Kv4.2 gene controlling functional expression of the repolarizing transient outward K+ current (Ito) and, thereby, AP duration. This mechanism, which might occur very early during the onset of hypertrophy, enhances Ca2+ entry by maintaining Ca2+ channel activation during prolonged AP. Both Ca2+-dependent facilitation and Ca2+-dependent down-regulation of Ito expression favour AP prolongation and, thereby, promote sustained voltage-gated Ca2+ entry used to enhance excitation–contraction (EC) coupling (with no change in the density of Ca2+ channels per se). These self-maintaining mechanisms of Ca2+ entry have significant functions in remodelling Ca2+ signalling during the cardiac AP. They might support a prominent role of Ca2+ channels in the establishment and progression of abnormal Ca2+ signalling during cardiac hypertrophy and congestive heart failure.