Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 203

Heterotrimeric G proteins transmit stimuli from plasmalemmal GPCRs to various
intracellular effectors, such as enzymes and ion channels. Associated signaling
mediators, such as heterotrimeric G proteins, adenylate cyclases, phospholipase-A2,
-C

-arrestin-1, GPCR kinases, A-
kinase-anchoring proteins, and protein kinase-A, among others, can be transferred
to the nuclear membrane and nucleus. Moreover, enzymes involved in the synthesis
and metabolism of phosphoinositides as well as in the processing of peptide ligands,
such as angiotensin-converting enzyme and endothelin-converting enzyme-1 can
localize to the nucleus.
Both

β , and -D, regulators of G-protein signaling, β

plasmalemmal and nuclear GPCRs can activate effectors, such as

G proteins, -arrestins, and nuclear protein kinases that modulate the activity

of transcription factors. G

β

subunits as well as effectors PKB and MAPK interact
with transcription factors, chromatin regulators such as histone deacetylases, and
DNA elements [ 354 ].
In addition, G

βγ

subunits regulate cellular signaling and organize the assembly
and transfer of receptor-based complexes in intracellular compartments, such as
the endoplasmic reticulum and Golgi body. Moreover, G

βγ

2 dimer can localize
in the nucleus, where it interacts directly with HDAC5 histone deacetylase [ 354 ].
The G

β 1 γ

5-RGS7 complex localizes to both the cytosol and nucleus. Protein RGS6
can also reside in the nucleus. In the nucleus, G

β

5 dimer complexes with the
transcriptional repressor adipocyte enhancer-binding protein AEBP1 and attenuates
its transcriptional repression. In addition, G

βγ

colocalizes with activating protein
AP1 in the nucleus and recruits HDACs to inhibit AP1 transcriptional activity.
Prenylation increases G

βγ

βγ amount associated with the glucocorticoid receptor

(NR3c1) in the nucleus.
Nuclear GPCRs launch classical pathways that produce and/or activate a second
messengers or stimulate the MAPK module or the PI3K-PKB axis, like those
initiated at the plasma membrane. Nonetheless, these receptors can directly regulate
DNA synthesis, histone modification, and gene transcription [ 354 ].

5.2.4.1 Nuclear “ -Adrenergic Receptors

In 1-adrenergic receptors launch the

Gs-AC-cAMP pathway responsible for the chronotropic and inotropic effects
of sympathetic stimulation.

cardiomyocytes, plasmalemmal β

-Adrenergic receptors can also interact with other
heterotrimeric G-protein subunits such as Gi subunit. Other signaling pathways rely
G-protein-coupled receptor kinases and

β

-Arrestins are implicated in
GPCR desensitization, hence suppression of the first wave of signals triggered at
the plasma membrane by G proteins, and internalization, which is associated with
an (eventually G-protein-independent) intracellular (endosomal) second wave of
cues.
In cardiomyocytes, whereas plasmalemmal

β -arrestins. β

1-adrenergic receptors play a pre-
dominant role in the regulation of cardiomyocyte contractility, plasmalemmal

β