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Calsarcins/Myozenins (Calsarcin-1 and Calsarcin-2) & Calcineurin A/B Antibodies
Calcineurin is a Ca/calmodulin-dependent serine-threonine phosphatase that plays an important role in transducing Ca-dependent signals in a variety of cell types. Calcineurin has also been shown to have a profound influence on the properties of striated muscle cells, including cardiac muscle. A novel family of striated muscle-specific calcineurin-interacting proteins called calsarcins or myozenins has been identified that interact and colocalize with the Z-disc protein alpha-actinin. Two isoform of calsarcins, Calsarcin-1 and Calsarcin-2, with specific expression pattern have been identified in human, rat and mouse. Calsarcins tether calcineurin to the sarcomere of cardiac and skeletal muscle. Besides calcineurin and a-actinin, calsarcins interact with other Z-disc proteins g-filamin, telethonin and TCAP. Because calcineurin responds to sustained, low amplitude calcium signals, calsarcins may serve to localize calcineurin in the vicinity of unique intracellular pool, where it can interact with specific upstream activators or downstream substrates. Therefore, calsarcins may play an important role in modulating the function and substrate specificity of calcineurin in striated muscle cells. Calsarcin-1 (CALS-1), also known as Myozenin-2 or MYOZ2, is a ~32 kDa protein (human/mouse 264-aa, ~88% identity). Amino acids 217-240 of calsarcin-1 are necessary for its interaction with a-actinin-2 in the Z-disc of sarcomeric muscle fibers. It is expressed, throughout the development-cycle, in all striated muscle tissues. However, CALS-1 expression is localized in slow-twitch fibers (soleus and plantaris), which depends on chronic motor neuron stimulation that results in sustained cellular calcium. Calsarcin-2/CALS-2 (variously termed Myozenin-1 and FATZ) ~34 kDa, human 299-aa, mouse 296-aa, ~30% identity with CALS-1) is a globular protein with central glycine-rich domain flanked by a-helical regions. CALS-2 is expressed transiently in heart during early embryogenesis and later becomes restricted to skeletal muscle with weaker signals in adult prostate, placenta and pancreas. In contrast to CALS-1, the expression of Calsarcin-2 is restricted to fast-twitch skeletal fiber (Gastrocnemius), which receives intermittent, high frequency stimulation and exhibit lower intracellular calcium concentration. Calsarcin-2 interacts with other Z-disc proteins g-Filamin, ACTN-2, ACTN-3 and TCAP and possibly modulates both g-filamin and a-actinin dimerization. Based on its binding partners, Calsarcin-2 has been suggested to play a central role in myofibrillogenesis and as a candidate for limb-girdle muscular dystrophy and other related neuromuscular disorders.
Calcineurin (also known as CALNA or CALNA1,
Calcineurin-alpha, Protein phosphatase 2B or PP2B) is the
Ca+/calmodulin-regulated protein phosphatase, first detected in skeletal muscle
and brain, has been found in from yeast to mammals. It is a heterodimers of two
subunits: Calcineurin B/CnB, the 19-kda Ca+-binding and regulatory subunit, and
Calcineurin A/CnA, ~61-kda catalytic subunit that is highly homologous with PP1
and PP2A. . Multiple catalytic subunits of calcineurin are derived from at least
2 structural genes, type 1 (calcineurin A-alpha) and type 2 (calcineurin A-beta,
CALNA2), each of which can produce additional alternatively spliced transcripts.
CnB belongs to the family of EF-hand Ca-binding proteins. Both CnB and
calmodulin are important for the activation of the phosphatase activity of
calcineurin. Calcineurin controls the production of many cytokines including
IL-2, TNF-alpha in the T-cell activation pathway. Calcineurin mediated
dephosphorylation of the nuclear factor of activated T-cells (NF-AT) is required
for NF-AT activation, nuclear translocation, and subsequent gene expression in
T-cells. The immunosuppressive drugs, such as FK506, inhibit activation of NF-AT
by calcineurin.
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