HDAC7, 188.8.131.52, Phospholamban, DAG, Ca-ATPase2, IP3 receptor, Na('+) extracellular region, Ryanodine receptor 1, <cytosol> ATP + <cytosol> H(,2)O + <cytosol> Ca('2+) = <cytosol> ADP + <cytosol> phosphate + <endoplasmic reticulum lumen> Ca('2+), <extracellular region> Ca('2+) = <cytosol> Ca('2+), IP3, MEF2, NCX1, CaMKK, AKAP6, Calcipressin 1, <endoplasmic reticulum lumen> Ca('2+) = <cytosol> Ca('2+), CREB1, Ca('2+) cytosol, Calcineurin A (catalytic), PLC-beta, <extracellular region> Na('+) + <cytosol> Ca('2+) = <cytosol> Na('+) + <extracellular region> Ca('2+), PP1-cat, CD44, HDAC5, NF-AT1(NFATC2), RhoGDI alpha, PtdIns(4,5)P2, cPKC (conventional), RhoA, CaMK IV, Calmodulin, G-protein beta/gamma, PKA-cat (cAMP-dependent), HDAC4, Na('+) cytosol, PP2A catalytic, Ca('2+) endoplasmic reticulum lumen, IP3R1, CaMK I, VIL2 (ezrin), FKBP12, ROCK2, Ca('2+) extracellular region, CaMK II
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++ transporting ( Ca-ATPase). 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 proteins.
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 ( PKA ) , 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 .
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 Ca('2+) .
The other target for Ca('2+) is a protein Ca lmodulin. Calcium-bound calmodulin associates with and activates serine/threonine phosphatase Calcineurin. Calcineurin 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 C alcium/calmodulin-dependent protein kinase kinase ( CaMKK). CaMKII and CaMKIV regulate transcription via phosphorylation of several transcription factors, including cAMP responsive element binding protein ( CREB) .
Another pathway of Ca('2+) -mediated transcription regulation is phosphorylation of Histone deacetylases ( HDAC4, HDAC5, and 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 .