Abstract
In spite of the widespread role of calmodulin (CaM) in cellular signaling, CaM mutations lead specifically to cardiac manifestations, characterized by remarkable electrical instability and a high incidence of sudden death at young age. Penetrance of the mutations is surprisingly high, thus postulating a high degree of functional dominance. According to the clinical patterns, arrhythmogenesis in CaM mutations can be attributed, in the majority of cases, to either prolonged repolarization (as in long-QT syndrome, LQTS phenotype), or to instability of the intracellular Ca2+ store (as in catecholamine-induced tachycardias, CPVT phenotype). This review discusses how mutations affect CaM signaling function and how this may relate to the distinct arrhythmia phenotypes/mechanisms observed in patients; this involves mechanistic interpretation of negative dominance and mutation-specific CaM-target interactions. Knowledge of the mechanisms involved may allow critical approach to clinical manifestations and aid in the development of therapeutic strategies for “calmodulinopathies,” a recently identified nosological entity.
Highlights
As other ions, Ca2+ is used as a charge carrier to modulate membrane potential; Ca2+ has a central role as a diffusible signaling molecule and as a trigger of diverse cellular functions
This led to the conclusion that Ca2+-dependent inactivation (CDI) and Ca2+-dependent facilitation (CDF) had different mechanisms, but that CaM binding to the IQ motif is involved in both cases
We recently investigated hiPSC-CMs from a patient with long QT syndrome (LQTS) phenotype and heterozygous carrier of the CALM1p.F142L mutation [80] (Figure 4)
Summary
Ca2+ is used as a charge carrier to modulate membrane potential; Ca2+ has a central role as a diffusible signaling molecule and as a trigger of diverse cellular functions While some of these are clearly complementary in achieving a functional goal (e.g., cAMP signaling in functional upregulation) and can coexist, others are devoted to apparently competing aims (e.g., apoptosis pathway) and need to be separated. This requires mechanisms allowing intracellular Ca2+ to act on its targets with high specificity. Active Ca2+ compartmentalization within organelles allows to keep “resting” Ca2+ concentration in the general (or “bulk”) cytosolic compartment at very low levels (around 10−7 M), i.e., below the threshold required to activate downstream effectors; at the same time, structural organization (e.g., T-tubules) allows very small Ca2+ fluxes to achieve high Ca2+ concentration in the specific subcellular compartment hosting the target effector [1]
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