Biomedical Engineering Reference
In-Depth Information
Table 6.10.
Main inward anion currents and corresponding channels in the heart (
i
f
: non-selective
cation current; Source: [
468
]). Sodium current (
i
Na
) due to cardiac voltage-gated sodium channels
controls action potential upstroke and cell excitability.
Current
Channel
Genes
i
Na
Na
V
1.5
SCNA5
SCN1B, SCN2B
i
Ca
,
L
Ca
V
1.2
CACNA1C, CACNL1A1
CACNB1-CACNB2, CACNA2D1
i
Ca
,
T
Ca
V
3.1
CACNA1H
i
f
HCN1, HCN2, HCN4
KCNE2
outward current, via reactive oxygen species produced by NADPH oxidase and
stress-activated kinases such as MAP3K5 and its main targets, P38MAPK and JNK
kinases [
599
]. Therefore, the MAP3K5-P38MAPK/JNK pathway participates in
cardiac ion channel remodeling.
Sustained elevation in cytosolic Ca
2
+
concentration stimulates PP3 that
dephosphorylates NFAT3 and promotes its translocation to the nucleus, thereby
reducing several repolarizing K
+
flux types (
i
K
,
to
and rapidly activating and slowly
inactivating K
+
currents
i
K
,
slow1
and
i
K
,
slow2
)[
599
]. Therefore, another pathway, the
Ca
2
+
-CamK2-PP3-NFAT3 axis, is involved in cardiac ion channel remodeling.
In mouse ventriculomyocytes with constitutive activation of PI3K
c1α
as well
as in exercise-trained mice, K
+
current amplitudes and cell size increase, but K
+
current density does not significantly differ from that in wild-type and untrained
mice, because K
V
channel expression rises in proportion to myocyte size in
adaptive cardiac hypertrophy [
600
]. Therefore, the PI3K-PKB pathway contributes
to cardiac ion channel remodeling.
56
6.4.1
Pacemaker Cells
Major currents in sinoatrial nodal as well as atrial cells correspond to fluxes of
sodium, potassium, and calcium ions (Tables
6.11
to
6.13
;Fig.
6.4
)[
601
-
603
].
Sinoatrial nodal cells are heterogeneous, hence exhibiting different types of action
potentials. A mathematical model that relies on a non-linear system of 10 first-order
ordinary differential equations has been proposed to represent the functioning of a
cardiac pacemaker cell [
604
].
56
Transcription factors of the FOXO family that are effectors of the PI3K
c1α
-PKB axis regulate the
promoter activity of several K
+
channel genes, such as KCNJ8 (K
IR
6.1), KCNJ11 (K
IR
6.2), and
AbcC8 (SUR1), as well as KCND2 (K
V
4.2), KCNB1 (K
V
2.1), KCNK3 (TASK1), and KCNIP2
(KChIP2) [
600
]. Furthermore, glycogen synthase kinase GSK3
β
, another mediator of PI3K
c1α
,
also controls the activity of several transcription factors, such as NFAT, GATA4, myocardin, MyC,
Jun, and
-catenin, many of which may bind to promoters of several K
+
channel subunit genes.
β
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