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Calmodulinopathy: Functional Effects of CALM Mutations and Their Relationship With Clinical Phenotypes

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Review

Calmodulinopathy: Functional Effects of CALM Mutations and Their Relationship With Clinical Phenotypes

Beatrice Badone et al. Front Cardiovasc Med.

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.

Keywords: Ca2+ handling; arrhythmia mechanisms; calmodulin mutations; ion channels; repolarization.

Figures

Figure 1
Figure 1
Representation of CaM sequence and relative disease-associated mutations. The letters identify amino acids directly involved in Ca2+ binding (within the EF-hands), or in the hinge region. Color-substituted amino acids represent mutations in the EF-hands (circles) or in the linkers (squares); colors correspond to the associated phenotype: catecholaminergic polymorphic ventricular tachycardia (CPVT, light blue), long QT syndrome (LQTS, red), idiopathic ventricular fibrillation (IVF, yellow), other unexplained sudden death (green). LQTS/CPVT overlap mutations are shown in shaded color. Modified from Crotti and Kotta, (11).
Figure 2
Figure 2
Model for CaM-dependent modulation of Cav1.2 channels (ICaL). CDI mechanism: in the channel closed state (Rest), the N-lobe of apo-CaM (N) is constitutively bound to a pre-IQ region (A) in the channel C-terminus. When the channel opens (Activation), the CaM C-lobe (C) binds to the entering Ca2+, which increases its affinity for the channel IQ-domain; this moves the channel inactivation particle (I) in the permeation path (Inactivation). CDF mechanism: holo-CaM binding to CaMKII promotes channel phosphorylation, which results in repulsion of the inactivation particle from the permeation pore (Facilitation). Modified from Maier and Bers (8).
Figure 3
Figure 3
CaM-dependent modulation of RyR2 channels. RyR2 closed state is stabilized by the interaction (zipping) between “terminal” and “central” regions of the N-terminal (cytosolic) tail of the protein. If such interaction is removed (unzipping), the channel closed state is destabilized. Apo-CaM binds to a domain distal to the “zipping” one, but the resulting conformation allosterically facilitates the zipping interaction, thus stabilizing RyR2 closed state. CaM and F-DPc10 (a peptide obstructing the zipping interaction) allosterically “compete” for binding to RyR2. Similarly, the unzipped state, promoted by drugs and reactive oxygen species which facilitate RyR2 opening, reduces RyR2 affinity for CaM (67). F-DPc10 is a peptide fragment designed to prevent the interaction between the central and N-terminal protein domains (a tool in testing the unzipping model). From Oda et al. (66).
Figure 4
Figure 4
Arrhythmogenic mechanism of CALM1 F142L from experiments in patient-derived hiPSC-CMs. Electrophysiology: (A) ICaL CDI (hatched area) was reduced; (B) CDI impairment led to APD prolongation and inadequate APD shortening at high pacing rate; (C) APD abnormalities led to loss of 1:1 response to fast pacing in a large % of F142L cells. Calcium handling: (D) Impaired ICaL CDI led to matching increments of Ca2+ influx and of the amplitude of Ca2+ transients (CaT); excitation/release gain (ER-gain) was unchanged, thus suggesting normal RyRs function. (E) In spite of enhanced Ca2+ influx, SR Ca2+ content was unchanged, thus implying compensation by homeostatic mechanisms. (F) The slope of the relationship between Na+/Ca2+ exchanger current (INCX) and Ca2+ concentration was unchanged, to indicate that homeostatic compensation did not involve changes in the expression of the exchanger. Asterisks denote significance of changes. Modified from ref. Rocchetti et al. (80).

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References

    1. Clapham DE. Calcium signaling. Cell (2007) 131:1047–58. 10.1016/j.cell.2007.11.028 - DOI - PubMed
    1. Ikura M. Calcium binding and conformational response in EF-hand proteins. Trends Biochem Sci. (1996) 21:14–7. 10.1016/S0968-0004(06)80021-6 - DOI - PubMed
    1. Luby-Phelps K, Hori M, Phelps JM, Won D. Ca2+-regulated dynamic compartmentalization of calmodulin in living smooth muscle cells. J Biol Chem. (1995) 270:21532–8. 10.1074/jbc.270.37.21532 - DOI - PubMed
    1. Deisseroth K, Heist EK, Tsien RW. Translocation of calmodulin to the nucleus supports CREB phosphorylation in hippocampal neurons. Nature (1998) 392:198. 10.1038/32448 - DOI - PubMed
    1. Berchtold MW, Villalobo A. The many faces of calmodulin in cell proliferation, programmed cell death, autophagy, and cancer. Biochim Biophys Acta Mol Cell Res. (2014) 1843:398–435. 10.1016/j.bbamcr.2013.10.021 - DOI - PubMed
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