RGD Reference Report - Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. - Rat Genome Database

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Calcium-calcineurin signaling in the regulation of cardiac hypertrophy.

Authors: Wilkins, BJ  Molkentin, JD 
Citation: Wilkins BJ and Molkentin JD, Biochem Biophys Res Commun. 2004 Oct 1;322(4):1178-91.
RGD ID: 1579951
Pubmed: PMID:15336966   (View Abstract at PubMed)
DOI: DOI:10.1016/j.bbrc.2004.07.121   (Journal Full-text)

Cardiac hypertrophy is a leading predicator of progressive heart disease that often leads to heart failure and a loss of cardiac contractile performance associated with profound alterations in intracellular calcium handling. Recent investigation has centered on identifying the molecular signaling pathways that regulate cardiac myocyte hypertrophy, as well as the mechanisms whereby alterations in calcium handling are associated with progressive heart failure. One potential focal regulator of cardiomyocyte hypertrophy that also responds to altered calcium handling is the calmodulin-activated serine/threonine protein phosphatase calcineurin (PP2B). Once activated by increases in calcium, calcineurin mediates the hypertrophic response through its downstream transcriptional effector nuclear factor of activated T cells (NFAT), which is directly dephosphorylated by calcineurin resulting in nuclear translocation. While previous studies have convincingly demonstrated the sufficiency of calcineurin to mediate cardiac hypertrophy and progressive heart failure, its necessity remains an area of ongoing investigation. Here we weigh an increasing body of literature that suggests a causal link between calcineurin signaling and the cardiac hypertrophic response and heart failure through the use of pharmacologic inhibitors (cyclosporine A and FK506) and genetic approaches. We will also discuss the manner in which calcineurin-NFAT signaling is negatively regulated in the heart through a diverse array of kinases and inhibitory proteins. Finally, we will discuss emerging theories as to the mechanisms whereby alterations in intracellular calcium handling might stimulate calcineurin within the context of a contractile cell continually experiencing calcium flux.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Left Ventricular Hypertrophy  IAGP 1579951 RGD 

Molecular Pathway Annotations    Click to see Annotation Detail View
Objects Annotated

Genes (Rattus norvegicus)
Nfatc2  (nuclear factor of activated T-cells 2)
Nfatc3  (nuclear factor of activated T-cells 3)
Nfatc4  (nuclear factor of activated T-cells 4)
Ppp3ca  (protein phosphatase 3 catalytic subunit alpha)
Ppp3cb  (protein phosphatase 3 catalytic subunit beta)
Ppp3cc  (protein phosphatase 3 catalytic subunit gamma)
Ppp3r1  (protein phosphatase 3, regulatory subunit B, alpha)
Ppp3r2  (protein phosphatase 3, regulatory subunit B, beta)

Genes (Mus musculus)
Nfatc2  (nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 2)
Nfatc4  (nuclear factor of activated T cells, cytoplasmic, calcineurin dependent 4)
Ppp3ca  (protein phosphatase 3, catalytic subunit, alpha isoform)
Ppp3cb  (protein phosphatase 3, catalytic subunit, beta isoform)
Ppp3cc  (protein phosphatase 3, catalytic subunit, gamma isoform)
Ppp3r1  (protein phosphatase 3, regulatory subunit B, alpha isoform (calcineurin B, type I))
Ppp3r2  (protein phosphatase 3, regulatory subunit B, alpha isoform (calcineurin B, type II))

Genes (Homo sapiens)
NFATC2  (nuclear factor of activated T cells 2)
NFATC3  (nuclear factor of activated T cells 3)
NFATC4  (nuclear factor of activated T cells 4)
PPP3CA  (protein phosphatase 3 catalytic subunit alpha)
PPP3CB  (protein phosphatase 3 catalytic subunit beta)
PPP3CC  (protein phosphatase 3 catalytic subunit gamma)
PPP3R1  (protein phosphatase 3 regulatory subunit B, alpha)
PPP3R2  (protein phosphatase 3 regulatory subunit B, beta)


Additional Information