Biomedical Engineering Reference
In-Depth Information
Ca
V
1 channels, ryanodine receptors, Ca
2
+
-activated Ca
2
+
release channels, and
sarcoplasmic reticulum Ca
2
+
SERCA2 ATPase. The latter controls Ca
2
+
reuptake
into the sarcoplasmic reticulum, after dissociation from phospholamban.
73
Adrenaline and noradrenaline released by the sympathetic system increase
calcium currents conducted by heteromeric Ca
V
1.2 channels of cardiomyocytes.
74
β
-Adrenergic signaling causes a 3- to 4-fold rise in calcium current due to the
activation of adenylate cyclase and inhibition of phosphodiesterases. Both activated
β
β
2-adrenergic receptors increase the channel activity via phosphorylation
by protein kinase-A in association with A-kinase-anchoring protein AKAP15. How-
ever, the calcium current predominantly results from activation of
1- and
β
1-adrenergic
receptors.
75
The sympathetic system stimulates the heart through
β
-adrenergic receptors.
β
β
About 75% of cardiac
1-receptors. They are distributed
throughout the sarcolemma and coupled to Gs-protein. Less abundant
-adrenergic receptors are
β
2-adrenergic
receptors reside predominantly in caveolae. Several other ion carriers exist in
caveolae of cardiomyocytes: voltage-dependent Na
+
channel, K
V
1.5 channel, Na
+
-
Ca
2
+
exchanger, pacemaker HCN4 channel, and Ca
V
1 channels.
76
β
2-Adrenergic
receptors signal via the set of cardiac Ca
V
1 channels of caveolae in ventriculomy-
ocyte [
454
]. Channel Ca
V
1 colocalizes with caveolin-3, a major structural protein
of caveolae in striated myocytes.
77
β
-Adrenergic receptor stimulates Gs protein, which activates adenylate cyclase,
producing cAMP, which in turn activates protein kinase-A (Fig.
6.9
). The latter
phosphorylates SERCA inhibitor phospholamban (lusitropic effect), Ca
V
1 channel,
ryanodine receptor, troponin-I (speed up dissociation of Ca
2
+
from myofilaments),
and myosin-binding protein-C. Increased L-type Ca
2
+
currents through Ca
V
1.2
73
Dephosphorylated phospholamban binds to SERCA2 and suppresses SERCA2 activity. PKA-
mediated phosphorylation of phospholamban unbinds it from SERCA2 to relieve SERCA2
inhibition.
74
Ca
V
1.2 channels are responsible for the major calcium current in cardiomyocytes which triggers
release of stored calcium from the sarcoplasmic reticulum for contraction.
75
β
2-Adrenergic receptor-mediated phosphorylation depends on intracellular calcium concentra-
tion that must be increased.
β
2-Adrenergic receptors do not significantly participate in the calcium
flux at basal calcium levels [
645
].
β
2-Adrenergic receptors associated with adenylate cyclases,
AKAP15, and calcium channels in the cardiomyocyte sarcolemma stimulate a small set of Ca
V
1.2
calcium channels. Protein kinase-C and calcium-calmodulin-dependent protein kinase-2 can also
phosphorylate voltage-gated calcium channels to increase the calcium influx.
76
These cardiac L-type voltage-gated Ca
2
+
channels outside of junctional complexes do not
strongly intervene in excitation-contraction coupling but regulate cellular functions.
77
Caveolae (Vol. 1 - Chap. 9. Intracellular Transport) are tiny invaginations of the plasma
membrane with cholesterol, sphingolipids, and caveolin. Many proteins involved in cellular Ca
2
+
activity are located in caveolae. They include IP
3
receptor, Na
+
-Ca
2
+
exchanger, Ca
2
+
AT P a s e ,
members of the transient receptor potential family. Caveolin-3, Ca
V
1.2 channel,
β
2-adrenergic
receptor (but not
α
i
proteins, adenylate cyclase, protein kinase-A,
and protein phosphatase-2 form signaling complexes in caveolae of cardiomyocytes.
β
α
s
and G
1-adrenoceptor), G
Search WWH ::
Custom Search