Entry |
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Name |
Calcium signaling pathway
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Description |
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).
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Class |
Environmental Information Processing; Signal transduction
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Pathway map |

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Disease |
H00441 | Progressive osseous heteroplasia |
H00746 | Hypokalemic periodic paralysis (HypoPP) |
H00755 | Acrokeratosis verruciformis |
H00787 | Congenital stationary night blindness |
H00801 | Familial thoracic aortic aneurysm and dissection |
H01019 | Catecholaminergic polymorphic ventricular tachycardia |
H01307 | Nonsyndromic congenital nail disorder |
H02019 | Familial male-limited precocious puberty |
H02026 | Familial hypocalciuric hypercalcemia |
H02258 | Tubular aggregate myopathy |
H02281 | Isolated anhidrosis with normal sweat glands |
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Drug |
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Other DBs |
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Orthology |
K05849 | solute carrier family 8 (sodium/calcium exchanger) |
K04129 | muscarinic acetylcholine receptor M1 |
K04131 | muscarinic acetylcholine receptor M3 |
K04133 | muscarinic acetylcholine receptor M5 |
K04141 | adrenergic receptor beta-1 |
K04142 | adrenergic receptor beta-2 |
K04143 | adrenergic receptor beta-3 |
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 |
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 |
K05208 | glutamate receptor ionotropic, NMDA 1 |
K05209 | glutamate receptor ionotropic, NMDA 2A |
K05211 | glutamate receptor ionotropic, NMDA 2C |
K05212 | glutamate receptor ionotropic, NMDA 2D |
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 |
K04157 | 5-hydroxytryptamine receptor 2 |
K04248 | lutropin-choriogonadotropic hormone 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 |
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 |
K10784 | T cell receptor alpha chain V region |
K10785 | T-cell receptor beta chain V region |
K06856 | immunoglobulin heavy chain |
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 |
K16896 | two pore calcium channel protein 1 |
K14077 | two pore calcium channel protein 2 |
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 |
K05865 | troponin C, slow skeletal and cardiac muscles |
K12042 | troponin C, skeletal muscle |
K07190 | phosphorylase kinase alpha/beta subunit |
K04515 | calcium/calmodulin-dependent protein kinase (CaM kinase) II [EC:2.7.11.17] |
K04348 | serine/threonine-protein phosphatase 2B catalytic subunit [EC:3.1.3.16] |
K06268 | serine/threonine-protein phosphatase 2B regulatory subunit |
K13755 | calcium/calmodulin-dependent 3',5'-cyclic nucleotide phosphodiesterase [EC:3.1.4.17] |
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Compound |
C01245 | D-myo-Inositol 1,4,5-trisphosphate |
C06124 | Sphingosine 1-phosphate |
C11556 | 1-Phosphatidyl-1D-myo-inositol 3,5-bisphosphate |
C13051 | Nicotinic acid adenine dinucleotide phosphate |
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Reference |
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Authors |
Berridge MJ, Bootman MD, Roderick HL. |
Title |
Calcium signalling: dynamics, homeostasis and remodelling. |
Journal |
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Reference |
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Authors |
Berridge MJ, Lipp P, Bootman MD. |
Title |
The versatility and universality of calcium signalling. |
Journal |
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Reference |
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Authors |
Wang MC, Dolphin A, Kitmitto A. |
Title |
L-type voltage-gated calcium channels: understanding function through structure. |
Journal |
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Reference |
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Authors |
Ferrier GR, Howlett SE. |
Title |
Cardiac excitation-contraction coupling: role of membrane potential in regulation of contraction. |
Journal |
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Reference |
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Authors |
Keef KD, Hume JR, Zhong J. |
Title |
Regulation of cardiac and smooth muscle Ca(2+) channels (Ca(V)1.2a,b) by protein kinases. |
Journal |
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Reference |
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Authors |
Hell JW, Appleyard SM, Yokoyama CT, Warner C, Catterall WA. |
Title |
Differential phosphorylation of two size forms of the N-type calcium channel alpha 1 subunit which have different COOH termini. |
Journal |
J Biol Chem 269:7390-6 (1994) |
Reference |
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Authors |
Yunker AM. |
Title |
Modulation and pharmacology of low voltage-activated ("T-Type") calcium channels. |
Journal |
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Reference |
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Authors |
Yakel JL. |
Title |
Calcineurin regulation of synaptic function: from ion channels to transmitter release and gene transcription. |
Journal |
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Reference |
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Authors |
Fukunaga K, Miyamoto E. |
Title |
A working model of CaM kinase II activity in hippocampal long-term potentiation and memory. |
Journal |
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Reference |
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Authors |
Della Rocca GJ, van Biesen T, Daaka Y, Luttrell DK, Luttrell LM, Lefkowitz RJ. |
Title |
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. |
Journal |
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Reference |
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Authors |
Furuichi T, Mikoshiba K. |
Title |
Inositol 1, 4, 5-trisphosphate receptor-mediated Ca2+ signaling in the brain. |
Journal |
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Reference |
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Authors |
Bruce JI, Straub SV, Yule DI. |
Title |
Crosstalk between cAMP and Ca2+ signaling in non-excitable cells. |
Journal |
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Reference |
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Authors |
Lee HC, Munshi C, Graeff R. |
Title |
Structures and activities of cyclic ADP-ribose, NAADP and their metabolic enzymes. |
Journal |
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Reference |
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Authors |
Crompton M. |
Title |
Mitochondrial intermembrane junctional complexes and their role in cell death. |
Journal |
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Reference |
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Authors |
Grewal SS, York RD, Stork PJ. |
Title |
Extracellular-signal-regulated kinase signalling in neurons. |
Journal |
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Reference |
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Authors |
Trushin SA, Pennington KN, Carmona EM, Asin S, Savoy DN, Billadeau DD, Paya CV. |
Title |
Protein kinase Calpha (PKCalpha) acts upstream of PKCtheta to activate IkappaB kinase and NF-kappaB in T lymphocytes. |
Journal |
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Reference |
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Authors |
Hutchins JR, Dikovskaya D, Clarke PR. |
Title |
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. |
Journal |
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Reference |
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Authors |
Tornquist K |
Title |
Sphingosine 1-phosphate, sphingosine kinase and autocrine calcium signalling in thyroid cells. |
Journal |
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Reference |
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Authors |
Feske S |
Title |
Immunodeficiency due to defects in store-operated calcium entry. |
Journal |
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Reference |
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Authors |
Giachini FR, Lima VV, Hannan JL, Carneiro FS, Webb RC, Tostes RC |
Title |
STIM1/Orai1-mediated store-operated Ca2+ entry: the tip of the iceberg. |
Journal |
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Reference |
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Authors |
Baba Y, Kurosaki T |
Title |
[Regulation of store-operated calcium entry by STIM1]. |
Journal |
Seikagaku 80:1123-8 (2008) |
Reference |
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Authors |
Galione A, Evans AM, Ma J, Parrington J, Arredouani A, Cheng X, Zhu MX |
Title |
The acid test: the discovery of two-pore channels (TPCs) as NAADP-gated endolysosomal Ca(2+) release channels. |
Journal |
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Reference |
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Authors |
Beard NA, Wei L, Dulhunty AF |
Title |
Ca(2+) signaling in striated muscle: the elusive roles of triadin, junctin, and calsequestrin. |
Journal |
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Reference |
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Authors |
Marty I |
Title |
Triadin regulation of the ryanodine receptor complex. |
Journal |
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Reference |
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Authors |
Arvanitis DA, Vafiadaki E, Sanoudou D, Kranias EG |
Title |
Histidine-rich calcium binding protein: the new regulator of sarcoplasmic reticulum calcium cycling. |
Journal |
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Related pathway |
ko04070 | Phosphatidylinositol signaling system |
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LinkDB |
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