(Ca2+)-dependent NFAT signaling in cardiac
Cardiac hypertrophy defined as a compensatory mechanism of the heart that helps to
maintain cardiac output during pathological states. Hypertrophy leads to pathologic
cardiac growth, and is associated with increased morbidity and mortality. Transcription
factor NF-AT3 (NFATc4) plays a critical role in
cardiac hypertrophic signaling. NF-AT3 signaling is
essential for normal cardiac valve and may be adapted specifically for transducing
pathologic signals into a hypertrophic response in the heart , .
GPCRs (G-protein coupled receptors) play an important role in the regulation of
cardiac function and adaptation to changes in hemodynamic burden. GPCRs involved in
cardiac hypertrophy are mainly represented by Angiotensin II receptor
type-1, Alpha-1A and Alpha-1B
adrenergic receptors and Beta-1 adrenergic
receptor. Angiotensin II is a multifunctional
hormone which influences functions of cardiovascular cells initiated by its interaction
with Angiotensin II receptor, type-1 , . Alpha-1 adrenergic receptors and
Beta-1 adrenergic receptor activated by
Phenylephrine and Noradrenaline
appear to be specifically required for a cardiac hypertrophic response , .
These GPCRs are coupled to three principal classes of heterotrimeric GTP-binding
proteins, G-alphaS, G-alphaI and G-alphaQ/11 which transduce signals towards
intracellular effectors such as enzymes and ion channels. G-proteins consist of the
subunits G-alpha (G-protein alpha-s,
G-protein alpha-i family, G-protein alpha-q/11
or G-protein alpha-q and
G-protein alpha-11) and G-beta/gamma
(G-proteins beta/gamma), which dissociate upon receptor
activation and independently activate intracellular signaling pathways , , , .
Activation of phospholipase C (PLC-beta1 and
PLC-beta3) leads to the hydrolysis of membrane
resulted in inositol-1,4,5-trisphosphate (IP3) and
diacylglycerol (DAG) production , . IP3 binds to IP3
receptor on the surface of the endoplasmic reticulum leading
to release of Ca(2+) ions. DAG
and Ca(2+) activate diverse isoforms of Protein kinase C
(PKC), including PKC-alpha,
PKC-beta and PKC-gamma , , . Increase of
DAG intracellular level leads to the opening of
DAG-sensitive ion channels (such as TRPC3 and
TRPC6), independently of PKC signaling , .
Activation of PKC also regulates changes in Ca(2+)
intracellular levels via phosphorylation of channels and pumps (such as
TRPC6, NCX1 and
L-type Ca(II) channel) that leads to the opening of channels
and Ca(2+) influx , , , , , followed by activation of Na+/H+ exchanger
regulatory factor, Calmodulin, physically interacts with
SLC9A1, thus resulting in activation of
Na+/H+ exchange by increases in
intracellular Ca(2+) level .
G-protein alpha-s activated by Beta-1
adrenergic receptor in cardiac tissues stimulates two Adenylate cyclases,
Adenylate cyclase type V and Adenylate cyclase
type VI, and subsequent cAMP (cyclic
Adenosine-3',5' Monophosphate) formation , , . Subsequently, activation of cAMP-dependent Protein kinase A (PKA) that
consists of regulatory (PKA-reg (cAMP-dependent)) and
catalytic subunits (PKA-cat (cAMP-dependent)) leads to
phosphorylation of a set of regulatory proteins, including activation of
L-type Ca(II) channel. The PKA and PKC signaling pathways
co-operate to increase this channel's activity by pre-association of the channel with PKC
isoforms and phosphorylation of L-type Ca(II) channel, alpha 1C
subunit, by PKA. It is a key mechanism of intracellular
Ca(2+) increase in the cardiac response to hormonal
Calcineurin A is a
calcium/calmodulin-activated, serine-threonine phosphatase that transmits signals to the
nucleus through dephosphorylation and translocation of nuclear transcription factors
NFATs . NF-AT3 (NF-ATc4) plays a critical
role in calcineurin-mediated cardiac hypertrophic signaling .
In the nucleus, NF-AT3 cooperates with other
transcription factors such as GATA-4,
MEF2D), HAND1 and
HAND2, leading to activation of transcription of genes,
essential for cardiac development, and, thus, hypertrophy , , .
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