Signal transduction Calcium signaling
Calcium Signaling
Calcium ( Ca('2+) ) is a common second messenger that regulates many processesin the cell (e.g., contraction, secretion, synaptic transmission, fertilization, nuclearpore regulation, transcription). In cardiac myocytes and muscle cells, Ca('2+)concentrations alternate between high levels during contraction and low levels duringrelaxation [1].
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 [2].
However, most cells have developed an additional pathway to generate localized andfast Ca('2+) signaling triggers deep inside the cell, which involves specializedintracellular Ca('2+) storage/release organelles. Primary such intracellularCa('2+) storage/release organelle in most cells is endoplasmic reticulum (ER). Instriated muscles, it is sarcoplasmic reticulum (SR). ER and SR contain specializedCa('2+) release channels: families of Ryanodine receptor and Inositol1,4,5-triphosphate receptor ( IP3 receptor ) [1].
Muscle relaxation is regulated by the subsequent return of Ca('2+) to the lumenof the sarcoplasmic reticulum through the action of Ca('2+) pumps, referred to asATPase Ca++ transporting ( Ca-ATPase). Ca-ATPase molecules are 110-kDatransmembrane proteins that transport Ca('2+) ions from the sarcoplasm to thelumen of the membrane system at the expense of ATP hydrolysis [3].
Activity of all sarcoplasmic reticulum channels is thoroughly regulated. And all threefamilies of channels are regulated by Ca('2+) [1], [4].In addition, their activities are regulated by specific proteins.
Phospholamban is an integral membrane protein highly expressed in cardiac andslow-twitch skeletal muscle fibers. It interacts with and regulates activity ofCa-ATPase2. Effects of Phospholamban on Ca-ATPase2 depend on thephosphorylation state of Phospholamban. When phosphorylated byCalcium/calmodulin-dependent protein kinase II ( CaMKII ) or Protein kinase A (PKA ) , Phospholamban binds to Ca-ATPase2 and increases theaffinity of the SR Ca('2+) pump for Ca('2+). DephosphorylatedPhospholamban binds and inhibits Ca-ATPase2 stabilizing enzyme in inactiveconformation [4].
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 largecytoplasmic scaffold domain, including the FK506 binding protein ( FKBP12 ) andPKA [5].
PKA phosphorylation of Ryanodine receptor 1 activates the channel.FKBP12 modulates of the Ryanodine receptor 1 channel, but specificmechanisms involved are still being investigated. It was proposed that FKBP12 canstabilize Ryanodine receptor 1 [5].
The IP3 receptor channels require the presence of Inositol 1,4,5-trisphosphate( IP3 ) for their activity [6]. And all three family of channels areregulated by Ca('2+) [1].
To prevent overloading of intracellular stores, the Ca('2+) that enteredthrough sarcolemma must be extruded from the cell. The Sodium/Calcium exchanger likeSolute carrier family 8 member 1 ( NCX1 ) is the primary mechanism by which theCa('2+) is extruded from the cell during relaxation. NCX1 is an integralmembrane protein that is expressed in many tissues. It was proposed that NCX1 ispart of a macromolecular complex which also includes Protein kinase A catalytic andregulatory subunits ( PKA-cat and PKA-reg ), Protein kinase C ( PKC), A kinase anchoring proteins ( AKAP6 ) and Phosphatases PP1 andPP2A. Kinases and phosphatases are possibly linked by protein AKAP6 [7].
Cytoplasmic Ca('2+) influences on the activity of numerousproteins. Several PKC (conventional PKC-alpha, PKC-beta andPKC-gamma ) are allosterically activated by Ca('2+) [8].
The other target for Ca('2+) is a protein Calmodulin. Calcium-bound calmodulin associates with and activates serine/threoninephosphatase C alcineurin. Calcineurin dephosphorylates NF-AT family oftranscription factors leading to theirs translocation to the nucleus [9].
Calcium-bound Calmodulin also activatescalcium/calmodulin-dependent protein kinases CaMKI, CaMKII, andCaMKIV, as well as C alcium/calmodulin-dependent protein kinase kinase (CaMKK). CaMKII and CaMKIV regulate transcription viaphosphorylation of several transcription factors, including cAMP responsive elementbinding protein ( CREB) [10].
Another pathway of Ca('2+) -mediated transcription regulation isphosphorylation of Histone deacetylases ( HDAC4, HDAC5, and HDAC7 ) byCaMKI and CaMKIV with subsequent inhibitory effects on Myelin expressionfactor 2 ( MEF2 ) transcriptional activity [11].
Membrane-spanning protein CD44 can regulate Ca('2+) efflux fromintracellular stores by activation of IP3 receptor. CD44 binds ERM familyof 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 itstranslocation to membrane, where it activates Rho-associated coiled-coil containingprotein kinases ( ROCK ) (ROCK1 and ROCK2). ROCK in turnphosphorylates and activates IP3 receptors [12].
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