Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 224

P21-Activated Kinase-1

P21-activated kinase-1, a Ser/Thr protein kinase activated by Rac1 and CDC42
GTPases, is located at the Z disc, sarcolemma, intercalated discs, and nuclear
membrane. Kinase PAK1 interacts with protein phosphatase-2, decreasing the
phosphorylation of cardiac troponin-I, and enhancing calcium sensitivity.

Phosphodiesterase-5A

cGMP-specific phosphodiesterase-5A localizes to the Z disc. It dissociates from the
Z disc during heart failure.

5.4 Cardiac Adenylate Cyclases and the cAMP Pathway

In cardiomyocytes as well as vascular endothelial and smooth muscle cells, cAMP
second messenger is involved in signaling transduction by acetylcholine, adeno-
sine, catecholamines, endothelin, glucagon, glucagon-like peptide-1, prostaglandins
(PGe1 and PGe2), and urocortin, among others. Signaling compartmentalization
and use of distinct effectors can explain distinct effects of cAMP signaling caused
by different messenger types.
First messengers target G-protein-coupled receptors, which subsequently acti-
vate transmembrane adenylate cyclase. Afterward, cAMP operates via 4 types of
effectors: (1) protein kinase-A; (2) RapGEF3 and RapGEF4 ( cAMP GEFs or EPACs);
(3) cyclic nucleotide-gated ion channels (CNG); and (4) phosphodiesterases (PDE).
The latter catabolize cAMP into AMP; however, PDE10a can be inhibited by cAMP
that acts either as a competitive antagonist or as an allosteric regulator [ 390 ].
Protein kinase-A contains 2 regulatory and 2 catalytic subunits. Once catalytic
subunits are liberated, PKA phosphorylate multiple effectors, such as enzymes (e.g.,
glycogen phosphorylase), transcription factors (e.g., CREB), nanomotors (troponin-
I, myosin-binding protein-C), ion channels (Ca V 1.2, ryanodine receptor), and other
signaling components.
On the other hand, soluble adenylate cyclase resides inside the nucleus and
mitochondria, as well as at microtubules and centrioles. In mitochondria, it couples
the electron transport chain with cellular respiration. It is activated by HCO 3
and/or calcium. Once they are internalized, plasmalemmal receptors of extracellular
messengers can signal via soluble adenylate cyclase. The latter is involved in
apoptosis in coronary endothelial cells and cardiomyocytes [ 390 ].