and Nav1.9 are primarily expressed peripheral sensory neurons, Nav1.

4
in skeletal muscle, and Nav1.6 in the central nervous system.
Nav1.5, encoded by the SCN5A gene, consists of four internally
homologous domains (I to IV) that are connected to each other by
cytoplasmic linkers (Fig. 2.1). Each domain consists of six
membranespanning
segments (S1 to S6), connected to each other by alternating
intracellular and extracellular peptide loops. The four domains are
arranged in a fourfold circular symmetry to form the channel. The
extracellular loops between S5 and S6 (termed the P segments) have a
unique primary structure in each domain (Fig. 2.2). The P segments
curve back into the membrane to form an ion-conducting central pore
whose structural constituents determine the selectivity and conductance
properties of the Na+ channel.1
Four auxiliary β subunits (Navβ1 to Navβ4, encoded by the genes
SCN1B to SCN4B, respectively) have been identified; each is a
glycoprotein
with a single membrane-spanning segment. The β subunits
modulate density, kinetics, voltage dependence of activation and
inactivation,
as well as surface expression of the Na+ channel.1
Na+ channels are the typical example of voltage-gated ion channels.
Na+ channels switch among three functional states: deactivated (closed),
activated (open), and inactivated (closed), depending on the membrane
potential (Em). These channel states control Na+ ion permeability
through the channel into the cardiomyocyte. Na+ channel activation
allows Na+ ion influx into the cell, and inactivation blocks the entry
of Na+ ions.
On excitation of the cardiomyocyte by electrical stimuli from adjacent
cells, its resting Em (approximately −85 mV) depolarizes. The positively
charged S4 segment of each domain of the α subunit functions as the
sensor of the transmembrane voltage; these segments are believed to
undergo rapid structural conformational changes in response to
membrane
depolarization, thus leading to channel opening (activation) from
its resting (closed) state and enabling a large and rapid influx of Na +
(inward Na+ current, INa) during the rapid upstroke (phase 0) of the
action potential in atrial, ventricular, and Purkinje cardiomyocytes. 2