Biology Reference
In-Depth Information
fast inward sodium (Na
+
) current (
I
Na
; for review see ref. [4]), and to
a lesser extent, the L-type Ca
2+
current (
I
Ca,L
; for review see ref. [5]).
The phase 1 notch, which is apparent in ventricular myocytes isolated
from epi- and mid-myocardial regions, but which is largely absent in
those isolated from the endocardium, is produced by activation of the
voltage-dependent transient outward potassium (K
+
) current (
I
to,1
). In
some species, a transient voltage-independent Ca
2+
-modulated Cl
−
current contributes to the phase 1 notch (
I
to,2
); however, this current is
not known to be expressed in human. The phase 2 plateau is a time
during which membrane conductance is very low, with potential being
determined by a delicate balance between small inward and outward
currents. The major inward plateau current is
I
Ca,L,
and major outward
plateau currents are generated by the rapid and slow-activating
delayed outward rectifier K
+
currents
I
Kr
and
I
Ks
, respectively, and
the plateau K
+
current
I
Kp
. Repolarization phase 3 is produced by the
hyperpolarizing activated inward rectifier K
+
current
I
K1
.
Three major ion transporters and exchangers shape properties of
the cardiac AP, Ca
2+
transient and influence long-term regulation of
intracellular ion concentrations. These are the sarcolemmal Na
+
-K
+
pump, the sarcolemmal Na
+
-Ca
2+
exchanger, and the SR Ca
2+
-ATPase.
The sarcolemmal Na
+
-K
+
pump extrudes three Na
+
ions while importing
two K
+
ions on each cycle. This pump functions to keep intracellular
Na
+
low, thereby maintaining the external versus internal gradient of
Na
+
, by extruding Na
+
that enters during each AP. Cycling of this
pump requires hydrolysis of one ATP molecule, and generates a net
outward movement of one positive charge, thus contributing to out-
ward membrane current (this current is not shown in figure 9.2) and
influencing resting membrane potential.
The sarcolemmal Na
+
-Ca
2+
exchanger imports three Na
+
ions for
every Ca
2+
ion extruded, yielding a net charge movement. It is driven
by both transmembrane voltage and intra- and extracellular Na
+
and
Ca
2+
ion concentrations. It functions in forward mode during diastole
(the time interval between successive cardiac action potentials), in
which case it extrudes Ca
2+
and imports Na
+
, thus generating a net
inward current (labeled
I
Na/Ca
in figure 9.2). It is the principal means by
which Ca
2+
is extruded from the myocyte following each AP, particu-
larly during the diastolic interval. Because of the voltage- and
Ca
2+
-sensitivity of the exchanger, experimental evidence indicates that
it can function in reverse mode during the plateau phase of the AP,
in which case it extrudes Na
+
and imports Ca
2+
, thus generating a net
outward current.
A second major cytoplasmic Ca
2+
extrusion mechanism is the SR
Ca
2+
-ATPase (figure 9.1b). Rather than extruding Ca
2+
from the cell,
this ATPase pumps Ca
2+
from the cytosol into the NSR. The SR Ca
2+
-
ATPase has both forward and reverse components [6], with the reverse
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