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
BRITE hierarchy

nt06120  Calcium signaling (viruses and bacteria)
nt06124  Chemokine signaling (viruses)
nt06150  Cytokine-cytokine receptor interaction (viruses)
nt06161  Human immunodeficiency virus type 1 (HIV-1)
nt06164  Kaposi sarcoma-associated herpesvirus (KSHV)
nt06167  Human cytomegalovirus (HCMV)
nt06220  Calcium signaling
nt06263  Hepatocellular carcinoma
nt06266  Non-small cell lung cancer
nt06273  Glioma
nt06410  Calcium signaling
nt06460  Alzheimer disease

Homo sapiens (human) [GN:hsa]

PMID:12838335

Berridge MJ, Bootman MD, Roderick HL.

Calcium signalling: dynamics, homeostasis and remodelling.

Nat Rev Mol Cell Biol 4:517-29 (2003)
DOI:10.1038/nrm1155

PMID:11413485

Berridge MJ, Lipp P, Bootman MD.

The versatility and universality of calcium signalling.

Nat Rev Mol Cell Biol 1:11-21 (2000)
DOI:10.1038/35036035

PMID:15111104

Wang MC, Dolphin A, Kitmitto A.

L-type voltage-gated calcium channels: understanding function through structure.

FEBS Lett 564:245-50 (2004)
DOI:10.1016/S0014-5793(04)00253-4

PMID:11299192

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)
DOI:10.1152/ajpheart.2001.280.5.H1928

PMID:11698232

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)
DOI:10.1152/ajpcell.2001.281.6.C1743

PMID:8125957

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)

PMID:15000521

Yunker AM.

Modulation and pharmacology of low voltage-activated ("T-Type") calcium channels.

J Bioenerg Biomembr 35:577-98 (2003)
DOI:10.1023/B:JOBB.0000008025.65675.37

PMID:9149541

Yakel JL.

Calcineurin regulation of synaptic function: from ion channels to transmitter release and gene transcription.

Trends Pharmacol Sci 18:124-34 (1997)
DOI:10.1016/S0165-6147(97)01046-8

PMID:10997573

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)
DOI:10.1016/S0168-0102(00)00139-5

PMID:9235901

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)
DOI:10.1074/jbc.272.31.19125

PMID:7861177

Furuichi T, Mikoshiba K.

Inositol 1, 4, 5-trisphosphate receptor-mediated Ca2+ signaling in the brain.

J Neurochem 64:953-60 (1995)
DOI:10.1046/j.1471-4159.1995.64030953.x

PMID:14572802

Bruce JI, Straub SV, Yule DI.

Crosstalk between cAMP and Ca2+ signaling in non-excitable cells.

Cell Calcium 34:431-44 (2003)
DOI:10.1016/S0143-4160(03)00150-7

PMID:10331643

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)
DOI:10.1007/978-1-4419-8740-2_13

PMID:11080247

Crompton M.

Mitochondrial intermembrane junctional complexes and their role in cell death.

J Physiol 529 Pt 1:11-21 (2000)
DOI:10.1111/j.1469-7793.2000.00011.x

PMID:10508738

Grewal SS, York RD, Stork PJ.

Extracellular-signal-regulated kinase signalling in neurons.

Curr Opin Neurobiol 9:544-53 (1999)
DOI:10.1016/S0959-4388(99)00010-0

PMID:12972622

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)
DOI:10.1128/MCB.23.19.7068-7081.2003

PMID:14517314

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)
DOI:10.1091/mbc.E03-02-0061

PMID:21338471

Tornquist K

Sphingosine 1-phosphate, sphingosine kinase and autocrine calcium signalling in thyroid cells.

Acta Physiol (Oxf) 204:151-7 (2012)
DOI:10.1111/j.1748-1716.2011.02265.x

PMID:22129055

Feske S

Immunodeficiency due to defects in store-operated calcium entry.

Ann N Y Acad Sci 1238:74-90 (2011)
DOI:10.1111/j.1749-6632.2011.06240.x

PMID:22002090

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)
DOI:10.1590/S0100-879X2011007500133

PMID:19172794

Baba Y, Kurosaki T

[Regulation of store-operated calcium entry by STIM1].

Seikagaku 80:1123-8 (2008)

PMID:19475418

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)
DOI:10.1007/s00424-009-0682-y

PMID:19434403

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)
DOI:10.1007/s00249-009-0449-6

PMID:26228554

Marty I

Triadin regulation of the ryanodine receptor complex.

J Physiol 593:3261-6 (2015)
DOI:10.1113/jphysiol.2014.281147

PMID:20807542

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)
DOI:10.1016/j.yjmcc.2010.08.021