Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 231

5.6.1 Natriuretic Peptides

A- and B-type natriuretic peptides reside not only in specific granules of myoen-
docrine cells, but also in the brain, adrenal medulla, and kidney.

5.6.1.1 Natriuretic Peptides Receptors and Effects

Atrial natriuretic peptide (ANP) regulates arterial blood pressure and cardiomyocyte
growth. It stimulates angiogenesis and metabolism. Its hypovolemic effect is
exerted on both the kidney and systemic microcirculation. Natriuretic peptides also
contribute to the nervous regulation of the cardiac frequency.
In patients with maladaptive cardiac hypertrophy and heart failure, ANP and
BNP levels markedly increase, without elevated cGMP formation and signaling.
Desensitization of GC2a results from post-translational modifications, particularly
dephosphorylation within the kinase homology (KH) domain [ 399 ].

Natriuretic Peptides Receptors

Transmembrane natriuretic peptide receptors (NP 1 -NP 2 ) that are particulate
guanylate cyclases act similarly to nitric oxide, which targets soluble guanylate cy-
clases, as they enhance acetylcholine release and vagal-triggered bradycardia [ 400 ].
Receptor GC2a consists of an extracellular ligand-binding domain, a short
membrane-spanning region, and an intracellular part with a kinase homology
(KH) and a coiled-coil dimerization domain as well as the C-terminal catalytic
guanylate cyclase (GC) region. In the absence of ligand, the KH domain is highly
phosphorylated and the catalytic activity of GC2a is repressed. Upon ANP binding,
a conformational change occurs that activates the cyclase domain [ 399 ].
Another receptor NP 3 that lacks the guanylate cyclase domain operates via
inhibitory subunit (Gi) of guanine nucleotide-binding protein and likely also as
clearance receptors for circulating peptides.

cGMP-Dependent Signaling of Guanylate Cyclase-A

Via its particulate guanylate cyclase-2A (pGC2a) receptor and intracellular cGMP
messenger, atrial natriuretic peptide supports endothelial permeability [ 401 ].
Under normal ANP concentration, the ANP-cGMP axis activates
cGMP-dependent protein kinase PKG1 that prevents Ca 2 + influx into cardiomy-
ocytes triggered by angiotensin-2-bound AT 1 receptor. Repression of Ca 2 + entry
results from stimulation of regulator of G-protein signaling RGS2 and inhibition of
transient receptor potential canonical TRPC3 and TRPC6 channels [ 399 ].