Biomedical Engineering Reference
In-Depth Information
In addition, cAMP stimulates the “funny” pacemaker hyperpolarization-
activated current (
i
f
). This current results from fluxes of Na
+
and K
+
ions
through hyperpolarization-activated, cyclic nucleotide-gated tetrameric channels
(HCN). Each monomer has 6 transmembrane domains with voltage sensors
and binding sites for cyclic nucleotides such as cAMP. The HCN channel is
predominantly produced in the sinoatrial node. However, several HCN isoforms
are also synthesized in cardiac Purkinje cells and atrio- and ventriculomyocytes.
The HCN channel is slowly activated by hyperpolarization at a range of voltages
that arise from constitutive pacemaker depolarization. This activation triggers the
next electrochemical wave generation and propagation.
A-kinase-anchoring proteins control PKA activity. In humans, AKAP10 variants
are associated with increased cardiac frequency and decreased heart rate variability,
hence decaying sensitivity to external stimuli. Protein AKAP10 modulates the
sensitivity of cardiomyocytes to vagus nerve stimuli [
608
].
Spontaneous, Rhythmic, Subplasmalemmal Ca
2
+
Oscillations
6.4.1.2
In the absence of sarcolemma depolarization, sinoatrial nodal pacemaker cells
are able to generate localized, rhythmic, submembrane Ca
2
+
oscillations due to
extraction via sarcoplasmic reticulum Ca
2
+
pumps and Ca
2
+
release via ryanodine
receptors. Calcium cycling by the sarcoplasmic reticulum, the so-called sinoatrial
Ca
2
+
clock, generates these rhythmic, spontaneous, local Ca
2
+
releases that depend
on the cAMP-PKA axis.
Spontaneous membrane depolarizations interrupt these spontaneous Ca
2
+
oscillations, as action potential activates Ca
V
1 channels to trigger Ca
2
+
release
from the sarcoplasmic reticulum. During the later phase of the depolarization,
ryanodine receptors are inactivated and Ca
2
+
is pumped back into its store to
replenish it. Once the inactivation of ryanodine receptor wanes, the spontaneous
release of Ca
2
+
via ryanodine receptors restarts.
The local increase in submembrane Ca
2
+
concentration generates an inward
current via Na
+
-Ca
2
+
exchangers that elevates the depolarization slope, ignites
plasmalemmal ion channels, and triggers the occurrence of action potential.
Activated
-adrenoceptors increase the submembrane Ca
2
+
oscillation
amplitude and reduce the period between sarcoplasmic reticulum Ca
2
+
release
triggered by prior action potential and onset of the local Ca
2
+
release during
the subsequent depolarization, hence causing earlier influx through Na
+
-Ca
2
+
exchangers and arrival of the next action potential [
609
].
Regulation of cardiac automaticity in sinoatrial cells is attributed to the
modulation of sarcolemmal ion currents by G-protein-coupled receptors of the
β
β
-adrenergic and cholinergic receptor classes (Table
6.14
). Modulation of GPCRs
of sinoatrial cell automaticity involves coupling via transmembrane voltage
and Ca
2
+
flux of sarcolemmal and intracellular proteins, mainly those that are
responsible for [
610
]: (1) the diastolic Na
+
-Ca
2
+
exchanger current; (2) magnitude
of spontaneous, rhythmic, local Ca
2
+
releases from the sarcoplasmic reticulum; and
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