Calcium (Ca('2+)) is a
common second messenger that regulates many processes in the cell (e.g., contraction,
secretion, synaptic transmission, fertilization, nuclear pore regulation, transcription).
In cardiac myocytes and muscle cells, Ca('2+) concentrations
alternate between high levels during contraction and low levels during relaxation .
Regulation of Ca('2+) concentration in the cell is
coupled with both, transmembrane channel and storage/release of organelles.
Ca('2+) entry across the surface membrane is realized via
Calcium channels (Ca(II) channels) and leads to elevated
Ca('2+) cytosol levels,
providing Ca('2+) trigger signals for a large number of
physiological processes, including muscle contraction .
However, most cells have developed an additional pathway to generate localized and
fast Ca('2+) signaling triggers deep inside the cell, which
involves specialized intracellular Ca('2+) storage/release
organelles. Primary such intracellular Ca('2+)
storage/release organelle in most cells is endoplasmic reticulum (ER). In striated
muscles, it is sarcoplasmic reticulum (SR). ER and SR contain specialized
Ca('2+) release channels: families of
Ryanodine receptor and Inositol 1,4,5-triphosphate receptor
(IP3 receptor) .
Muscle relaxation is regulated by the subsequent return of
Ca('2+) to the lumen of the sarcoplasmic reticulum through
the action of Ca('2+) pumps, referred to as ATPase Ca++
Ca-ATPase molecules are 110-kDa transmembrane proteins that
transport Ca('2+) ions from the sarcoplasm to the lumen of
the membrane system at the expense of ATP hydrolysis .
Activity of all sarcoplasmic reticulum channels is thoroughly regulated. And all three
families of channels are regulated by Ca('2+) , . In addition, their activities are regulated by specific
Phospholamban is an integral membrane protein highly
expressed in cardiac and slow-twitch skeletal muscle fibers. It interacts with and
regulates activity of Ca-ATPase2. Effects of
Phospholamban on Ca-ATPase2
depend on the phosphorylation state of Phospholamban.
When phosphorylated by Calcium/calmodulin-dependent protein kinase II
(CaMKII) or Protein kinase A
Phospholamban binds to
Ca-ATPase2 and increases the affinity of the SR
Ca('2+) pump for Ca('2+).
Dephosphorylated Phospholamban binds and
inhibits Ca-ATPase2 stabilizing enzyme in
inactive conformation .
Ryanodine receptor 1 on the surface of SR is the major
calcium (Ca('2+)) release channel required for skeletal
muscle excitation-contraction coupling. Ryanodine receptor 1
function is modulated by proteins that bind to its large cytoplasmic
scaffold domain, including the FK506 binding protein
(FKBP12) and PKA .
PKA phosphorylation of Ryanodine receptor
1 activates the channel. FKBP12 modulates of
the Ryanodine receptor 1 channel, but specific mechanisms
involved are still being investigated. It was proposed that FKBP12
can stabilize Ryanodine receptor 1 .
The IP3 receptor channels require the presence of
Inositol 1,4,5-trisphosphate (IP3) for their activity . And all three family of channels are regulated by
To prevent overloading of intracellular stores, the
Ca('2+) that entered through sarcolemma must be extruded
from the cell. The Sodium/Calcium exchanger like Solute carrier family 8 member 1
(NCX1) is the primary mechanism by which the
Ca('2+) is extruded from the cell during relaxation.
NCX1 is an integral membrane protein that is expressed in
many tissues. It was proposed that NCX1 is part of a
macromolecular complex which also includes Protein kinase A catalytic and regulatory
subunits (PKA-cat and PKA-reg),
Protein kinase C (PKC), A kinase anchoring proteins
(AKAP6) and Phosphatases PP1
and PP2A. Kinases and phosphatases are possibly linked by
protein AKAP6 .
Cytoplasmic Ca('2+) influences on the
activity of numerous proteins. Several PKC (conventional
PKC-alpha, PKC-beta and
PKC-gamma) are allosterically activated by
The other target for Ca('2+) is a protein
calmodulin associates with and activates serine/threonine phosphatase
dephosphorylates NF-AT family of transcription factors leading to theirs translocation to
the nucleus .
Calcium-bound Calmodulin also activates
calcium/calmodulin-dependent protein kinases CaMKI,
CaMKII, and CaMKIV, as well as
Calcium/calmodulin-dependent protein kinase kinase
(CaMKK). CaMKII and
CaMKIV regulate transcription via phosphorylation of several
transcription factors, including cAMP responsive element binding protein
Another pathway of Ca('2+) -mediated
transcription regulation is phosphorylation of Histone deacetylases (HDAC4,
HDAC7) by CaMKI and CaMKIV
with subsequent inhibitory effects on Myelin
expression factor 2 (MEF2) transcriptional activity .
Membrane-spanning protein CD44 can regulate
Ca('2+) efflux from intracellular stores by activation of
IP3 receptor. CD44 binds ERM
family of proteins (VIL2 (ezrin), RDX
(radixin), MSN (moesin)). VIL2
(ezrin) action results in the release of Ras homolog gene family, member A
(RhoA) from Rho GDP dissociation inhibitor (GDI) alpha
(RhoGDI) and its translocation to membrane, where it
activates Rho-associated coiled-coil containing protein kinases
(ROCK) (ROCK1 and
ROCK2). ROCK in turn
phosphorylates and activates IP3 receptors .
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