Biomedical Engineering Reference
In-Depth Information
Ad/NAd
ACh
+
M2R
+
βAdR
ACase
Gs
Gi
ACaseGs
cAMP
Gi
AKAP
cAMP
mitochondrion
PKA
PKA
Cam
−
VDCC
RC
−
PLb
SERCA
−
TN−I
uniporter
NCX
NCX
myosin
actin
PMCA
Ca
influx
efflux
Fig. 6.9
β
-Adrenergic
and
M
2
muscarinic
interacting
receptors
and
CMC
functioning
(Source: [
464
]).
channels by activated
-adrenergic receptors require phosphorylation by protein
kinase-A anchored to the channel via an AKAP15 protein. Proteins AKAP15 and
PKA form an inhibitory complex [
646
].
A-kinase-anchoring protein splice variant AKAP18
β
complexes with Ca
V
1and
ryanodine channels. Another proteic complex that consists of SERCA2, phospho-
lamban, AKAP18
α
δ
, and PKA coordinates PKA phosphorylation of phospholamban
-adrenergic regulation of Ca
2
+
reuptake into the sarcoplasmic reticulum [
647
].
Muscarinic M
2
receptor activation can either decrease or increase cAMP con-
centrations, whether these receptors interfere with
and
β
β
1- or
β
2-adrenergic receptors,
respectively [
648
].
Both compartmentation and dynamics in cyclic adenosine monophosphate and
protein kinase-A signaling in cardiomyocytes influence cardiac inotropy. Activation
cAMP by protein kinase-A corresponds to a rate-limiting node of PKA pathway
downstream from the
-adrenergic receptor.
78
Prostaglandin E1 stimulates higher
PKA activity in the cytosol than at the sarcolemma, likely due to differences in
cAMP diffusion [
649
]. Restricted diffusion, cAMP degradation by phosphodiester-
ases, and cAMP accumulation near protein kinase-A contribute to both spatial and
temporal signaling variations.
β
78
Synthesis of cAMP can greatly exceed requirements for PKA activation.
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