Biomedical Engineering Reference
In-Depth Information
).
83
Intracellular Ca
2
+
can modulate func-
tioning of Na
+
channel. Calmodulin regulates Na
+
channel gating on binding.
Kinase CamK2 exerts acute effect on
isoform (
C
CamK2
specific CamK2
δ
δ
C
Na
V
channel gating that is independent of
calmodulin.
Calmodulin and CamK2 differ in their mode of inactivation of cardiac
C
Na
V
channels [
443
]. Enzyme CamK2
α
shifts the voltage dependence of Na
V
channel by
approximately
5 mV, hastens recovery from inactivation, lowers entry into inter-
mediate or slow inactivation, and heightens persistent (late) flux [
443
]. Calmodulin
alone reproduces CamK2-induced changes, but does not modify recovery from
inactivation and entry into slow or intermediate inactivation in normal guinea pig
ventriculomyocytes.
84
Regulatory
+
β
1and
β
2 subunits link to ankyrin-2 and -3 (or ankyrin-B and -G).
Interactions between
β
1 subunits and ankyrins are regulated by Tyr phosphorylation
of
1 subunits localize to intercalated discs with
connexin-43 and N-cadherin; non-phosphorylated proteins to other parts of the
sarcolemma [
445
]. Epidermal growth factor receptors and cytosolic protein Tyr
kinase Fyn as well as protein Tyr phosphatase (non-receptor) PTPn3 target Na
V
1.5
channels.
In cardiomyocytes, ankyrin-2 and -3 anchor integral membrane proteins, such as
ion channels, exchangers, and transporters to the actin and spectrin cytoskeletons.
Ankyrins may not only act as adaptors for Na
V
1.5 anchoring to the plasma
membrane, but also mediators of adequate transfer to intercalated discs and other
parts of the sarcolemma [
445
].
A pool of Na
V
1.5 channels colocalizes with caveolin-3 and dystrophin in
caveolae. This pool may be recruited upon
β
1 subunits. Phosphorylated
β
-adrenergic stimulation, in a PKA-
independent, but Gs-dependent manner [
445
].
85
β
5.10.2
Sodium-Calcium Exchangers
Sodium-calcium exchangers (NCX; Vol. 3 - Chap. 3. Main Classes of Ion Channels
and Pumps) yield inward or outward Ca
2
+
motions and outward or inward Na
+
fluxes, respectively, with the ratio of 3 Na
+
for 1 Ca
2
+
, whether the intracellular
concentration
Na
+
]
Ca
2
+
]
i
is high. Sodium-calcium exchangers induce slow
contractions. The unitary conductance for Ca
2
+
of Na
+
-Ca
2
+
exchanger is smaller
[
i
or
[
83
Enzyme CamK2
is mainly synthesized in neurons.
84
On the other hand, using a different experimental setting in rabbit and mouse ventriculomyocytes,
acute and chronic overexpression of
α
C
CamK2
, hence Ca
2
+
- and CamK2-dependent phosphory-
δ
lation of Na
V
1.5, shift voltage dependence by
6 mV, enhance intermediate inactivation, slow
recovery from inactivation, and raise the persistent, inward current [
444
].
85
In Duchenne muscle dystrophy, caveolin-3 is overexpressed, but concentrations of dystrophin
and its associated proteins decay in skeletal muscles as well as the heart.
−
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