Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 254

5.10.1 Voltage-Gated Sodium Channels

In mammals, 10 subunits of voltage-gated sodium channels are encoded by

10 genes (SCN1A-SCN5A and SCN7A-SCN11A). In some body's tissues, these
α

α

subunits, which are encoded by 4 genes
(SCN1B-SCN4B). The number of Na V channels can be extended by alternative
mRNA splicing. Differences in functional properties of Na + channel isoforms result
from unique conductances in specific cell types [ 439 ].
In mammalian hearts, Na V 1.5 isoform (encoded by the SCN5A gene) determines
Na + flux in atrial and ventricular myocytes. It is characterized by rapid activation
and inactivation kinetics. It opens and closes at specific stages of cardiac activity
in response to voltage change. Entry into the inactivated state is very fast (

subunits associate with accessory β

1ms).
It controls the magnitude and duration of voltage-dependent Na + currents ( i Na )in
cardiomyocytes.
In humans, splice variants of cardiac Na V 1.5 channel exist in both embryonic
and adult hearts [ 440 ]. Although alternative splicing during Na V 1.5 synthesis is
age- and gender-independent, it is species-dependent, as Na V 1.5d is not detected in
mouse heart. Voltage-dependent Na + currents generated by Na V 1.5d is markedly
reduced with respect to that through Na V 1.5 channel, without difference between
intracellular transfer of these 2 isoforms.
Cardiac voltage-gated sodium channels Na V 1.5 cause action potential upstroke
(fast depolarization). Once inactivated, Na V 1.5 channels may reopen, thereby
generating a depolarizing inward current after the plateau phase of action potential.
Glycosylated membrane protein Na V 1.5 interacts with

<

4).
In sinoatrial node pacemaker cells, Na V 1.5 activity couples pacemaker cells to
cells surrounding them within the sinoatrial node, as any impairment of impulse
initiation causes sinus bradycardia [ 441 ]. Furthermore, it is involved in impulse
propagation through the sinoatrial node as well as between the sinoatrial node and
atrial cells.

β subunits ( β 1- β

5.10.1.1 Na V 1.5 Regulation in Cardiomyocytes

In cardiomyocytes, protein kinase-A is mainly activated by -adrenergic receptors

that raise intracellular cAMP level. Upon phosphorylation by cAMP-dependent
protein kinase-A, cardiac Na V 1.5 channel gating remains unchanged, but the bulk
conductance rises, as the number of functional channels increases. This elevation in
plasmalemmal Na V 1.5 density results from heightened exocytosis of these channels
from multiple intracellular storage pools [ 442 ].
In addition to protein kinase-A and -C, Na V 1.5 channels are regulated by
calmodulin and calmodulin-dependent protein kinase CamK2, particularly cardiac-

β