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Page 168 Genovese et al. Cancer Drug Resist 2018;1:164-80 I http://dx.doi.org/10.20517/cdr.2018.10

The microRNA miR-1 targets Sorcin specifically and non-redundantly; miR-1 decreases Sorcin levels,
while the antagomiR-1 increases Sorcin expression ; treatment with miR-1 determines Ca signaling
[36]
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dysregulation, especially at cardiac level.

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Sorcin contributes to regulate Ca homeostasis and cardiac excitation-contraction-relaxation processes.
Excitation-contraction-relaxation is a fast (800 ms) process, started by the electrical excitation of
cardiomyocytes by a wave of depolarization that opens voltage-dependent Na channels located in the
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T-tubules, determining a rapid membrane depolarization and Ca influx via voltage-operated Ca channels
(mainly Cav1 L-type channels). Cav1 channels (with four subunits Cav1.1, Cav1.2, Cav1.3, Cav1.4) are
juxtaposed to ryanodine receptors (RyRs), i.e., sarcoplasmic reticulum (SR) or ER Ca release channels.
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Ca entry via Cav1 increases Ca concentration near RyRs, triggering Ca release from the SR. This flux
further raises the free intracellular Ca concentration [Ca ] of the cardiomyocyte: Ca binds to troponin
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I
C and triggers contraction. For relaxation to take place, RyR is closed and Ca is pumped out of the cytosol,
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mainly via the SR Ca -ATPase (SERCA), which pumps Ca back into the SR, and the sarcolemmal (and
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mitochondrial) Na /Ca exchanger (NCX) : [Ca ] decreases rapidly and Ca dissociation from the
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[37]
myofilaments can occur. i
Sorcin is able to interact with all the channels, exchangers and pumps responsible for Ca fluxes during the
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excitation-contraction-relaxation process, and to regulate them. Sorcin modulates Cav1, by interacting with
its Cav1.2 (CACNA1C) subunit with its C-terminal domain, slowing its Ca -dependent inactivation and
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stimulating voltage-dependent inactivation of Cav1-dependent Ca currents [13,14] .
Sorcin also Ca -dependently interacts with RyR2, the most expressed cardiac RyR, and strongly inhibits
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it, thereby reducing Ca efflux from SR/ER by decreasing RyR mean open time and frequency of open
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[16]
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event [8,15,17] . Sorcin is also able to interact with SERCA and to activate it , and to activate NCX via Ca -
dependent interaction of the respective C-terminal, calcium binding domains; Sorcin overexpression in
cardiomyocytes has also been associated with increased NCX activity [19,38] . Fast rates of association and of
dissociation between Sorcin and NCX allows NCX regulation on a “beat to beat” basis.
Overall, Sorcin regulates the excitation-contraction-relaxation processes in the heart and muscle: Sorcin
terminates the excitation-contraction processes, by inhibiting Ca -induced Ca release by the SR, helps
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[Ca ] decreasing and induces relaxation by inhibiting RyR2-dependent calcium release from the SR, by
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activating SERCA2-dependent calcium pumping from cytosol to the SR and by increasing NCX-dependent
Ca efflux through the sarcolemma (and possibly into the mitochondrion) [Figure 3].
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Sorcin phosphorylation alters its Ca -dependent activation, its translocation to the SR and the ability to
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regulate RyR2 activity. Sorcin is hyperphosphorylated in the failing heart; this increases Sorcin translocation
to the SR membrane and the SR Ca content and possibly results in the reduction of SR stress, in the
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reduction of basal [Ca ] and in improvement of cardiac relaxation [16,23,39] .
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i
The mutation F112L, located in the EF3 hand and associated with a familiar form of hypertrophic
cardiomyopathy and hypertension, as other mutations in the EF3 and/or in the D-helix of Sorcin decreases
the capacity of Sorcin to interact with RyR and to modulate SR Ca release, and determines complex cardiac
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alterations [15,40] . In failing heart, levels of SERCA2a and of RyR2 are often decreased, and consequent altered
cytosolic Ca transients lead to abnormal contraction. Sorcin overexpression in mice increases cardiac
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contractility in the normal heart and determines a rescue of the abnormal contractile function of the diabetic
heart, possibly due to improved Ca transients [40-43] , while Sorcin KO mice present ventricular arrhythmia
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and sudden death when challenged by acute stress .
[44]