Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 257

2 subunits regulate the excitation-contraction
coupling in the cardiomyocyte [ 450 ]. Depolarization-induced Ca 2 + entry through
Ca V 1.2 channels contributes to the duration of the action potential plateau.
Channel Ca V 1.2 releases a relatively small and localized amount of calcium
through the sarcolemma. The amount of Ca 2 + influx during depolarization is
limited by Ca 2 + -dependent inactivation of the cytosolic side of the channels by
calmodulin bound to the channels [ 451 ]. However, Ca 2 + currents through Ca V 1.2
control the main calcium flux by the release from the sarcoplasmic reticulum
through ryanodine channels that interact with closely apposed Ca V 1.2 channels.
In turn, Ca 2 + release from the sarcoplasmic reticulum contributes to the Ca 2 + -
dependent inactivation of the calcium current (double-negative feedback) [ 452 ].
These feedbacks require interaction with Ca 2 + -calmodulin and a channel motif IQ
of

Major myocardial α 2 δ 1and β

1 subunit [ 449 ].
In ventriculomyocytes, small clusters of Ca V 1.2 channels are functionally and
structurally coupled, hence enabling concerted openings of adjacent channels.
Calcium spark may be higher in couplons with clustered Ca V 1.2 channels than in
couplons with independent Ca V 1.2 channels. Sarcolemmal Ca V 1.2 channels form
clusters of various sizes to coordinate their gating upon membrane depolarization.
Binding of Ca V 1.2 channels via their C-termini enables allosteric activation of
adjoining channels [ 453 ]. Coordinated opening of Ca V 1.2 clusters, together with
coincident activation of independently gated channels, amplifyies Ca 2 + influx for
an optimized excitation-contraction coupling. Protein AKAP5 may determine the
size and promote the stability of Ca V 1.2 clusters. In addition, like protein kinase-A,
oligomerization of Ca V 1.2 channels shifts the voltage dependence of activation of
Ca V 1.2 to more hyperpolarized potentials to enhance the signaling robustness.
A subgroup of Ca V 1.2 channels localizes to caveolae with caveolin-3 in
ventriculomyocytes. They form a signaling complex with

α

2-adrenergic receptors,
adenylate cyclase, protein kinase-A, and protein phosphatase-2 [ 454 ].

β

Ca V 3

Density of Ca V 3 channels is large in ventricular Purkinje cells (involved in action
potential transmission rather than contraction) and atriomyocytes (atrial contraction
does not play a major role in atrium emptying), but it is small in most ventriculomy-
ocytes. Channel Ca V 3 inactivates very rapidly. Contractions initiated by Ca 2 + entry
in ventricular Purkinje cells via Ca V 3 are characterized by a longer delay to the
onset of sarcomere shortening and slower rates of shortening and relaxation [ 455 ].
Another mechanism, voltage-activated Ca 2 + release, activated directly by
the membrane depolarization without Ca 2 + entry, can cause Ca 2 + transient
currents [ 456 ]. This additional mechanism that is depressed in heart failure depends
on internal cAMP concentration [ 457 ]. Phosphorylations can then occur via the
ACase-PKA and Ca 2 + -calmodulin-dependent kinase pathways to regulate the
cardiac contraction strength.