Biomedical Engineering Reference
In-Depth Information
Table 6.14.
Model of the autonomic modulation of a cardiac pacemaker cell (Source: [
610
];
AChR: cholinergic receptor; AR: adrenergic receptor;
i
Ca
,
T
: T-type Ca
2
+
current (Ca
V
3.1);
i
K
,
r
: rapid inwardly rectifying K
+
current (K
V
11.1);
i
NaCaX
:Na
+
-Ca
2
+
exchanger current;
i
sus
:
sustained (steady), essentially Na
+
current). Varying intracellular cAMP concentration couples
intracellular and plasmalemmal clocks via phosphorylation by cAMP-dependent protein kinase A
(PKA) of phospholamban and Ca
V
1.3 channels that generate L-type Ca
2
+
current (
i
Ca
,
L
)and
trigger activity of ryanodine receptor on the sarcoplasmic reticulum. Acetylcholine slows the
cardiac clock via ACh-activated K
+
current (
i
K
ACh
)viaG
dimeric subunit of G protein. Both
amplitude and phase of spontaneous, local Ca
2
+
release can be assigned mainly by functioning
of ryanodine receptors and sarco(endo)plasmic reticulum Ca
2
+
ATPase (SERCA) subjected to the
inhibition of phospholamban on the one hand and Ca
V
1.3 channels and Na
+
-Ca
2
+
exchanger on
the other that all regulate subplasmalemmal Ca
2
+
fluxes.
βγ
Components
Elements
Intracellular Ca
2
+
clock
SERCA-phospholamban (reuptake),
Ryanodine receptor (release)
Subsarcolemmal Ca
2
+
current that
influences the transmembrane potential
βγ
Sarcolemmal clock
G
-stimulated
i
K
ACh
cAMP-activated
i
f
Refueling PKA-activated
i
Ca
,
L
Clearance
i
NaCaX
β
AR-stimulated
i
K
,
r
i
Ca
,
T
i
sus
Nervous control
Gs-coupled
β
AR
Gi-coupled AChR
Activation or inhibition of
the cAMP-PKA pathway
(3) spontaneous action potential firing rate that is modulated by
-adrenergic and
cholinergic receptors (firing rate increase and decrease, respectively). In addition
to intracellular Ca
2
+
transient triggered by the action potential, spontaneous, local
Ca
2
+
releases from the sarcoplasmic reticulum beneath the sarcolemma creating
multiple, relatively synchronous, locally propagating Ca
2
+
wavelets during the
late part of diastolic depolarization. The sarcoplasmic reticulum behaves as an
intracellular Ca
2
+
oscillator. Spontaneous Ca
2
+
release from the sarcoplasmic
reticulum depends on the Ca
2
+
pumping capability of the sarcoplasmic reticulum,
hence phospholamban that is regulated by the cAMP-PKA axis. Phospholamban
phosphorylation by protein kinase-A relieves its inhibition on SERCA pumps.
Protein kinase-A also phosphorylates ryanodine receptors. Local Ca
2
+
releases
activate the electrogenic operation of the sarcolemmal Na
+
-Ca
2
+
exchanger (NCX)
and generate an inward current that yields a steep rising depolarization phase [
610
].
β
β
-Adrenergic and cholinergic receptors shorten or prolong the period of local Ca
2
+
releases, as assessed by the duration between peak of Ca
2
+
transient that results
from action potential and maximum of spontaneous, local Ca
2
+
releases.
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