Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 247

CA

GRK

−

cytokine R ErbB2/3/4

IGF1R β AR

GPCR

Gs

cAMP

PKA

RC VDCC

RC

JaK

Ca

MAP3K

Ca CamK2

SR SR

SERCA PLb

PLb

SERCA

MAP2K

Ca

STAT

PDE5A

calpain3

PI3K

calcineurin

myosin

MAPK titin T−Cap

MLP

actin

PAK1

PKB sarcomere

PP2A

M Z

Z

PKC

genes

NF κ B

nucleus

Fig. 5.14 Cytokine receptors, HERs, and insulin-like growth factor-1 receptor (IGF1R) activate
the Janus kinase-signal transducer and activator of transcription (JaK-STAT) pathway, mitogen-
activated protein kinase (MAPK) pathway, and phosphatidylinositol 3-kinase-protein kinase-B
(PI3K-PKB) pathway, to regulate gene expression (Source: [ 416 ]). Calcium-activated PP3 (cal-
cineurin) dephosphorylates NFAT transcription factors involved in cardiac remodeling. Mechanical
stresses stimulate Z-disc sensors. The titin-telethonin-muscle-specific LIM protein (MLP) sensor
binds PP3 for mechanotransduction. Excitation-contraction coupling requires calcium ions.
Calcium fluxes govern myofilament contraction and relaxation, particularly via Ca V 1.2, or L-type
voltage-dependent calcium channel (VDCC), ryanodine channel (RC), and sarcoplasmic reticulum
calcium ATPase (SERCA) associated with its inhibitor phospholamban (PLb). The activity of these
3 calcium channels is regulated by protein kinase-A (PKA) and calcium-calmodulin-dependent
kinase-2 (CamK2). PKA is stimulated by G-protein-coupled receptors, such as the β -adrenergic
receptor ( β AR). Protein kinase PKC (PKC), located at the Z disc, regulates cardiomyocyte
contractility and hypertrophy. p21-Activated kinase-1 (PAK1) interacts with protein phosphatase-
2A (PP2A), targeting troponin-I and enhancing calcium sensitivity. Calpain-3 activates NF κ B.
Phosphodiesterase-5A (PDE5A) dissociates from the Z disc during heart failure. In heart failure,
GRK2 desensitizes G-protein activation of ACase.