Signal transduction - Calcium signaling

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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 Calmodulin. 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 Calcium/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].

References:

  1. Fill M, Copello JA
    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
  5. Reiken S, Lacampagne A, Zhou H, Kherani A, Lehnart SE, Ward C, Huang F, Gaburjakova M, Gaburjakova J, Rosemblit N, Warren MS, He KL, Yi GH, Wang J, Burkhoff D, Vassort G, Marks AR
    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 : 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

  1. Fill M, Copello JA
    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
  5. Reiken S, Lacampagne A, Zhou H, Kherani A, Lehnart SE, Ward C, Huang F, Gaburjakova M, Gaburjakova J, Rosemblit N, Warren MS, He KL, Yi GH, Wang J, Burkhoff D, Vassort G, Marks AR
    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 : 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

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