Pathway maps

Signal transduction_Calcium signaling
Signal transduction_Calcium signaling

Object List (links open in MetaCore):

HDAC7,, 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 Signaling

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 [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 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 ) [1].

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 [3].

Activity of all sarcoplasmic reticulum channels is thoroughly regulated. And all three families 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 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 [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 large cytoplasmic scaffold domain, including the FK506 binding protein ( FKBP12 ) and PKA [5].

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 [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 are regulated by Ca('2+) [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 [7].

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+) [8].

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 [9].

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) [10].

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 [11].

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 [12].


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    Ryanodine receptor calcium release channels. Physiological reviews 2002 Oct;82(4):893-922
  2. Catterall WA
    Structure and regulation of voltage-gated Ca2+ channels. Annual review of cell and developmental biology 2000;16:521-55
  3. Asahi M, McKenna E, Kurzydlowski K, Tada M, MacLennan DH
    Physical interactions between phospholamban and sarco(endo)plasmic reticulum Ca2+-ATPases are dissociated by elevated Ca2+, but not by phospholamban phosphorylation, vanadate, or thapsigargin, and are enhanced by ATP. The Journal of biological chemistry 2000 May 19;275(20):15034-8
  4. Simmerman HK, Jones LR
    Phospholamban: protein structure, mechanism of action, and role in cardiac function. Physiological reviews 1998 Oct;78(4):921-47
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    PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure. The Journal of cell biology 2003 Mar 17;160(6):919-28
  6. Gudermann T, Mederos y Schnitzler M, Dietrich A
    Receptor-operated cation entry--more than esoteric terminology? Science's STKE [electronic resource] : signal transduction knowledge environment. 2004 Jul 20;2004(243):pe35
  7. Schulze DH, Muqhal M, Lederer WJ, Ruknudin AM
    Sodium/calcium exchanger (NCX1) macromolecular complex. The Journal of biological chemistry 2003 Aug 1;278(31):28849-55
  8. Way KJ, Chou E, King GL
    Identification of PKC-isoform-specific biological actions using pharmacological approaches. Trends in pharmacological sciences 2000 May;21(5):181-7
  9. Im SH, Rao A
    Activation and deactivation of gene expression by Ca2+/calcineurin-NFAT-mediated signaling. Molecules and cells 2004 Aug 31;18(1):1-9
  10. Soderling TR
    The Ca-calmodulin-dependent protein kinase cascade. Trends in biochemical sciences 1999 Jun;24(6):232-6
  11. McKinsey TA, Zhang CL, Olson EN
    MEF2: a calcium-dependent regulator of cell division, differentiation and death. Trends in biochemical sciences 2002 Jan;27(1):40-7
  12. Singleton PA, Bourguignon LY
    CD44v10 interaction with Rho-kinase (ROK) activates inositol 1,4,5-triphosphate (IP3) receptor-mediated Ca2+ signaling during hyaluronan (HA)-induced endothelial cell migration. Cell motility and the cytoskeleton 2002 Dec;53(4):293-316