KEGG   PATHWAY: ko04020
ko04020                     Pathway                                
Calcium signaling pathway
Ca2+ that enters the cell from the outside is a principal source of signal Ca2+. Entry of Ca2+ is driven by the presence of a large electrochemical gradient across the plasma membrane. Cells use this external source of signal Ca2+ by activating various entry channels with widely different properties. The voltage-operated channels (VOCs) are found in excitable cells and generate the rapid Ca2+ fluxes that control fast cellular processes. There are many other Ca2+-entry channels, such as the receptor-operated channels (ROCs), for example the NMDA (N-methyl-D-aspartate) receptors (NMDARs) that respond to glutamate. There also are second-messenger-operated channels (SMOCs) and store-operated channels (SOCs).
The other principal source of Ca2+ for signalling is the internal stores that are located primarily in the endoplasmic/sarcoplasmic reticulum (ER/SR), in which inositol-1,4,5-trisphosphate receptors (IP3Rs) or ryanodine receptors (RYRs) regulate the release of Ca2+. The principal activator of these channels is Ca2+ itself and this process of Ca2+-induced Ca2+ release is central to the mechanism of Ca2+ signalling. Various second messengers or modulators also control the release of Ca2+. IP3, which is generated by pathways using different isoforms of phospholipase C (PLCbeta, delta, epsilon, gamma and zeta), regulates the IP3Rs. Cyclic ADP-ribose (cADPR) releases Ca2+ via RYRs. Nicotinic acid adenine dinucleotide phosphate (NAADP) may activate a distinct Ca2+ release mechanism on separate acidic Ca2+ stores. Ca2+ release via the NAADP-sensitive mechanism may also feedback onto either RYRs or IP3Rs. cADPR and NAADP are generated by CD38. This enzyme might be sensitive to the cellular metabolism, as ATP and NADH inhibit it.
The influx of Ca2+ from the environment or release from internal stores causes a very rapid and dramatic increase in cytoplasmic calcium concentration, which has been widely exploited for signal transduction. Some proteins, such as troponin C (TnC) involved in muscle contraction, directly bind to and sense Ca2+. However, in other cases Ca2+ is sensed through intermediate calcium sensors such as calmodulin (CALM).
Environmental Information Processing; Signal transduction
Pathway map
ko04020  Calcium signaling pathway

D04789  Lubeluzole (USAN/INN)
Other DBs
GO: 0019722
K05849  solute carrier family 8 (sodium/calcium exchanger)
K05850  P-type Ca2+ transporter type 2B [EC:]
K04129  muscarinic acetylcholine receptor M1
K04131  muscarinic acetylcholine receptor M3
K04133  muscarinic acetylcholine receptor M5
K04266  adenosine receptor A2a
K04267  adenosine receptor A2b
K04141  adrenergic receptor beta-1
K04142  adrenergic receptor beta-2
K04143  adrenergic receptor beta-3
K04144  dopamine receptor D1
K05840  dopamine receptor D5
K04150  histamine receptor H2
K04160  5-hydroxytryptamine receptor 4
K04161  5-hydroxytryptamine receptor 5
K04162  5-hydroxytryptamine receptor 6
K04163  5-hydroxytryptamine receptor 7
K04632  guanine nucleotide-binding protein G(s) subunit alpha
K04633  guanine nucleotide-binding protein G(olf) subunit alpha
K08041  adenylate cyclase 1 [EC:]
K08042  adenylate cyclase 2 [EC:]
K08043  adenylate cyclase 3 [EC:]
K08044  adenylate cyclase 4 [EC:]
K08047  adenylate cyclase 7 [EC:]
K08048  adenylate cyclase 8 [EC:]
K08049  adenylate cyclase 9 [EC:]
K04345  protein kinase A [EC:]
K05852  phospholamban
K05853  P-type Ca2+ transporter type 2A [EC:]
K23450  sarcoplasmic reticulum histidine-rich calcium-binding protein
K16059  stromal interaction molecule 1
K18196  stromal interaction molecule 2
K16056  calcium release-activated calcium channel protein 1
K16057  calcium release-activated calcium channel protein 2
K16058  calcium release-activated calcium channel protein 3
K04850  voltage-dependent calcium channel L type alpha-1C
K04851  voltage-dependent calcium channel L type alpha-1D
K04853  voltage-dependent calcium channel L type alpha-1F
K04857  voltage-dependent calcium channel L type alpha-1S
K04344  voltage-dependent calcium channel P/Q type alpha-1A
K04849  voltage-dependent calcium channel N type alpha-1B
K04852  voltage-dependent calcium channel R type alpha-1E
K04854  voltage-dependent calcium channel T type alpha-1G
K04855  voltage-dependent calcium channel T type alpha-1H
K04856  voltage-dependent calcium channel T type alpha-1I
K04809  nicotinic acetylcholine receptor alpha-7
K05215  P2X purinoceptor 1
K05216  P2X purinoceptor 2
K05217  P2X purinoceptor 3
K05218  P2X purinoceptor 4
K05219  P2X purinoceptor 5
K05220  P2X purinoceptor 7
K05221  P2X purinoceptor 6
K05208  glutamate receptor ionotropic, NMDA 1
K05209  glutamate receptor ionotropic, NMDA 2A
K05211  glutamate receptor ionotropic, NMDA 2C
K05212  glutamate receptor ionotropic, NMDA 2D
K04961  ryanodine receptor 1
K04962  ryanodine receptor 2
K04963  ryanodine receptor 3
K23449  triadin
K23468  calsequestrin 1
K23445  calsequestrin 2
K00476  aspartate beta-hydroxylase [EC:]
K04322  cysteinyl leukotriene receptor 1
K04323  cysteinyl leukotriene receptor 2
K04130  muscarinic acetylcholine receptor M2
K04135  adrenergic receptor alpha-1A
K04136  adrenergic receptor alpha-1B
K04137  adrenergic receptor alpha-1D
K04166  angiotensin II receptor type 1
K04197  endothelin receptor type A
K04198  endothelin receptor type B
K03914  coagulation factor II (thrombin) receptor
K04603  metabotropic glutamate receptor 1
K04604  metabotropic glutamate receptor 5
K04169  gastrin-releasing peptide receptor
K04149  histamine receptor H1
K04157  5-hydroxytryptamine receptor 2
K04248  lutropin-choriogonadotropic hormone receptor
K04211  neurotensin receptor 1
K04229  oxytocin receptor
K04226  arginine vasopressin receptor 1A
K04227  arginine vasopressin receptor 1B
K04297  leukotriene B4 receptor 2
K04279  platelet-activating factor receptor
K04258  prostaglandin E receptor 1
K04260  prostaglandin E receptor 3
K04262  prostaglandin F receptor
K03915  bradykinin receptor B1
K03916  bradykinin receptor B2
K04222  tachykinin receptor 1
K04223  tachykinin receptor 2
K04224  tachykinin receptor 3
K04264  thromboxane A2 receptor
K04282  thyrotropin-releasing hormone receptor
K04194  cholecystokinin A receptor
K04195  cholecystokinin B receptor
K04189  C-X-C chemokine receptor type 4
K04634  guanine nucleotide-binding protein G(q) subunit alpha
K04635  guanine nucleotide-binding protein subunit alpha-11
K04636  guanine nucleotide-binding protein subunit alpha-14
K04637  guanine nucleotide-binding protein subunit alpha-15
K04357  epidermal growth factor
K04359  platelet-derived growth factor subunit A
K17386  platelet-derived growth factor subunit B
K05450  platelet derived growth factor C/D
K18496  fibroblast growth factor 1
K18497  fibroblast growth factor 2
K04358  fibroblast growth factor
K22603  fibroblast growth factor 19
K22429  fibroblast growth factor 21
K22428  fibroblast growth factor 23
K05448  vascular endothelial growth factor A
K16858  vascular endothelial growth factor B
K05449  vascular endothelial growth factor C/D
K05451  nerve growth factor, alpha
K02582  nerve growth factor, beta
K05460  hepatocyte growth factor
K23441  hepatocyte growth factor-like protein
K05452  glial cell derived neurotrophic factor
K04361  epidermal growth factor receptor [EC:]
K05083  receptor tyrosine-protein kinase erbB-2 [EC:]
K05084  receptor tyrosine-protein kinase erbB-3 [EC:]
K05085  receptor tyrosine-protein kinase erbB-4 [EC:]
K04363  platelet-derived growth factor receptor alpha [EC:]
K05089  platelet-derived growth factor receptor beta [EC:]
K04362  fibroblast growth factor receptor 1 [EC:]
K05093  fibroblast growth factor receptor 2 [EC:]
K05094  fibroblast growth factor receptor 3 [EC:]
K05095  fibroblast growth factor receptor 4 [EC:]
K05096  FMS-like tyrosine kinase 1 [EC:]
K05097  FMS-like tyrosine kinase 4 [EC:]
K05098  kinase insert domain protein receptor [EC:]
K03176  neurotrophic tyrosine kinase receptor type 1 [EC:]
K04360  neurotrophic tyrosine kinase receptor type 2 [EC:]
K05101  neurotrophic tyrosine kinase, receptor type 3 [EC:]
K05099  proto-oncogene tyrosine-protein kinase Met [EC:]
K05100  macrophage-stimulating 1 receptor [EC:]
K05126  proto-oncogene tyrosine-protein kinase Ret [EC:]
K10784  T cell receptor alpha chain V region
K10785  T-cell receptor beta chain V region
K06856  immunoglobulin heavy chain
K05857  phosphatidylinositol phospholipase C, delta [EC:]
K05858  phosphatidylinositol phospholipase C, beta [EC:]
K01116  phosphatidylinositol phospholipase C, gamma-1 [EC:]
K05859  phosphatidylinositol phospholipase C, gamma-2 [EC:]
K05860  phosphatidylinositol phospholipase C, epsilon [EC:]
K05861  phosphatidylinositol phospholipase C, zeta [EC:]
K04958  inositol 1,4,5-triphosphate receptor type 1
K04959  inositol 1,4,5-triphosphate receptor type 2
K04960  inositol 1,4,5-triphosphate receptor type 3
K01242  ADP-ribosyl cyclase 1 [EC:]
K16896  two pore calcium channel protein 1
K14077  two pore calcium channel protein 2
K04992  mucolipin 1
K04993  mucolipin 2
K04994  mucolipin 3
K04718  sphingosine kinase [EC:]
K20858  calcium uniporter protein, mitochondrial
K05862  voltage-dependent anion channel protein 1
K15040  voltage-dependent anion channel protein 2
K15041  voltage-dependent anion channel protein 3
K05863  solute carrier family 25 (mitochondrial adenine nucleotide translocator), member 4/5/6/31
K09565  peptidyl-prolyl isomerase F (cyclophilin D) [EC:]
K05865  troponin C, slow skeletal and cardiac muscles
K12042  troponin C, skeletal muscle
K02183  calmodulin
K00871  phosphorylase kinase gamma subunit [EC:]
K07190  phosphorylase kinase alpha/beta subunit
K00907  myosin-light-chain kinase [EC:]
K08794  calcium/calmodulin-dependent protein kinase I [EC:]
K04515  calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:]
K05869  calcium/calmodulin-dependent protein kinase IV [EC:]
K04348  serine/threonine-protein phosphatase 2B catalytic subunit [EC:]
K06268  serine/threonine-protein phosphatase 2B regulatory subunit
K13240  nitric-oxide synthase, brain [EC:]
K13241  nitric-oxide synthase, inducible [EC:]
K13242  nitric-oxide synthase, endothelial [EC:]
K13755  calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase [EC:]
K05871  focal adhesion kinase 2 [EC:]
K00911  1D-myo-inositol-triphosphate 3-kinase [EC:]
K02677  classical protein kinase C alpha type [EC:]
K19662  classical protein kinase C beta type [EC:]
K19663  classical protein kinase C gamma type [EC:]
C00002  ATP
C00004  NADH
C00076  Calcium cation
C00165  Diacylglycerol
C00575  3',5'-Cyclic AMP
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01330  Sodium cation
C06124  Sphingosine 1-phosphate
C11556  1-Phosphatidyl-1D-myo-inositol 3,5-bisphosphate
C13050  Cyclic ADP-ribose
C13051  Nicotinic acid adenine dinucleotide phosphate
Berridge MJ, Bootman MD, Roderick HL.
Calcium signalling: dynamics, homeostasis and remodelling.
Nat Rev Mol Cell Biol 4:517-29 (2003)
Berridge MJ, Lipp P, Bootman MD.
The versatility and universality of calcium signalling.
Nat Rev Mol Cell Biol 1:11-21 (2000)
Wang MC, Dolphin A, Kitmitto A.
L-type voltage-gated calcium channels: understanding function through structure.
FEBS Lett 564:245-50 (2004)
Ferrier GR, Howlett SE.
Cardiac excitation-contraction coupling: role of membrane potential in regulation of contraction.
Am J Physiol Heart Circ Physiol 280:H1928-44 (2001)
Keef KD, Hume JR, Zhong J.
Regulation of cardiac and smooth muscle Ca(2+) channels (Ca(V)1.2a,b) by protein kinases.
Am J Physiol Cell Physiol 281:C1743-56 (2001)
Hell JW, Appleyard SM, Yokoyama CT, Warner C, Catterall WA.
Differential phosphorylation of two size forms of the N-type calcium channel alpha 1 subunit which have different COOH termini.
J Biol Chem 269:7390-6 (1994)
Yunker AM.
Modulation and pharmacology of low voltage-activated ("T-Type") calcium channels.
J Bioenerg Biomembr 35:577-98 (2003)
Yakel JL.
Calcineurin regulation of synaptic function: from ion channels to transmitter release and gene transcription.
Trends Pharmacol Sci 18:124-34 (1997)
Fukunaga K, Miyamoto E.
A working model of CaM kinase II activity in hippocampal long-term potentiation and memory.
Neurosci Res 38:3-17 (2000)
Della Rocca GJ, van Biesen T, Daaka Y, Luttrell DK, Luttrell LM, Lefkowitz RJ.
Ras-dependent mitogen-activated protein kinase activation by G protein-coupled receptors. Convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase.
J Biol Chem 272:19125-32 (1997)
Furuichi T, Mikoshiba K.
Inositol 1, 4, 5-trisphosphate receptor-mediated Ca2+ signaling in the brain.
J Neurochem 64:953-60 (1995)
Bruce JI, Straub SV, Yule DI.
Crosstalk between cAMP and Ca2+ signaling in non-excitable cells.
Cell Calcium 34:431-44 (2003)
Lee HC, Munshi C, Graeff R.
Structures and activities of cyclic ADP-ribose, NAADP and their metabolic enzymes.
Mol Cell Biochem 193:89-98 (1999)
Crompton M.
Mitochondrial intermembrane junctional complexes and their role in cell death.
J Physiol 529 Pt 1:11-21 (2000)
Grewal SS, York RD, Stork PJ.
Extracellular-signal-regulated kinase signalling in neurons.
Curr Opin Neurobiol 9:544-53 (1999)
Trushin SA, Pennington KN, Carmona EM, Asin S, Savoy DN, Billadeau DD, Paya CV.
Protein kinase Calpha (PKCalpha) acts upstream of PKCtheta to activate IkappaB kinase and NF-kappaB in T lymphocytes.
Mol Cell Biol 23:7068-81 (2003)
Hutchins JR, Dikovskaya D, Clarke PR.
Regulation of Cdc2/cyclin B activation in Xenopus egg extracts via inhibitory phosphorylation of Cdc25C phosphatase by Ca(2+)/calmodulin-dependent protein [corrected] kinase II.
Mol Biol Cell 14:4003-14 (2003)
Tornquist K
Sphingosine 1-phosphate, sphingosine kinase and autocrine calcium signalling in thyroid cells.
Acta Physiol (Oxf) 204:151-7 (2012)
Feske S
Immunodeficiency due to defects in store-operated calcium entry.
Ann N Y Acad Sci 1238:74-90 (2011)
Giachini FR, Lima VV, Hannan JL, Carneiro FS, Webb RC, Tostes RC
STIM1/Orai1-mediated store-operated Ca2+ entry: the tip of the iceberg.
Braz J Med Biol Res 44:1080-7 (2011)
Baba Y, Kurosaki T
[Regulation of store-operated calcium entry by STIM1].
Seikagaku 80:1123-8 (2008)
Galione A, Evans AM, Ma J, Parrington J, Arredouani A, Cheng X, Zhu MX
The acid test: the discovery of two-pore channels (TPCs) as NAADP-gated endolysosomal Ca(2+) release channels.
Pflugers Arch 458:869-76 (2009)
Beard NA, Wei L, Dulhunty AF
Ca(2+) signaling in striated muscle: the elusive roles of triadin, junctin, and calsequestrin.
Eur Biophys J 39:27-36 (2009)
Marty I
Triadin regulation of the ryanodine receptor complex.
J Physiol 593:3261-6 (2015)
Arvanitis DA, Vafiadaki E, Sanoudou D, Kranias EG
Histidine-rich calcium binding protein: the new regulator of sarcoplasmic reticulum calcium cycling.
J Mol Cell Cardiol 50:43-9 (2011)
ko04010  MAPK signaling pathway
ko04070  Phosphatidylinositol signaling system
ko04210  Apoptosis
ko04720  Long-term potentiation
ko04730  Long-term depression

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