Calcium signaling

{{Short description|Intracellular communication process}} [[File:Calcium Signaling Pathway.png|thumb|305x305px|Shows Ca²⁺ release from the endoplasmic reticulum through phospholipase C (PLC) pathway.]]'''Calcium signaling''' is the use of calcium ions (Ca²⁺) to communicate and drive intracellular processes, often as a step in signal transduction. Ca²⁺ is important for a wide variety of cellular signaling pathways. Once Ca²⁺ enters the cytosol of the cytoplasm it exerts allosteric regulatory effects on many enzymes and proteins. Ca²⁺ signaling can activate certain ion channels for short term changes (like changes to electrochemical gradients) in the cell. For longer-term changes (like changes in gene transcription<ref>{{cite journal |last1=Johnson |first1=Claire M. |last2=Hill |first2=Caroline S. |last3=Chawla |first3=Sangeeta |last4=Treisman |first4=Richard |last5=Bading |first5=Hilmar |title=Calcium Controls Gene Expression via Three Distinct Pathways That Can Function Independently of the Ras/Mitogen-Activated Protein Kinases (ERKs) Signaling Cascade |journal=The Journal of Neuroscience |date=15 August 1997 |volume=17 |issue=16 |pages=6189–6202 |doi=10.1523/JNEUROSCI.17-16-06189.1997 |pmid=9236230 |pmc=6568353 }}</ref>), Ca²⁺ can act as a second messenger through indirect signal transduction pathways, such as in G protein-coupled receptor pathways. Calcium signaling plays a role in muscle contraction, fertilization, cell growth, synaptic plasticity and apoptosis.

== Calcium Concentration Regulation == The resting concentration of Ca²⁺ in the cytoplasm is normally maintained around 100 nM. This is 20,000- to 100,000-fold lower than typical extracellular concentration.<ref name="pmid18083096" /><ref name="Demaurex_2016">{{cite journal |vauthors=Demaurex N, Nunes P |date=April 2016 |title=The role of STIM and ORAI proteins in phagocytic immune cells |journal=American Journal of Physiology. Cell Physiology |volume=310 |issue=7 |pages=C496-508 |doi=10.1152/ajpcell.00360.2015 |pmc=4824159 |pmid=26764049}}</ref> To maintain this low concentration, Ca²⁺ is naturally buffered by different organelles and proteins within the cell. To change Ca²⁺ levels in the cytosol, it can be actively pumped out of the cell (from the cytosol to the extracellular space), into the endoplasmic reticulum (ER), or into the mitochondria. Calcium signaling occurs when the cell is stimulated to release Ca²⁺ ions from intracellular stores (the ER or mitochondria), or when Ca²⁺ enters the cell through plasma membrane ion channels.<ref name="pmid18083096">{{cite journal | vauthors = Clapham DE | title = Calcium signaling | journal = Cell | volume = 131 | issue = 6 | pages = 1047–58 | date = December 2007 | pmid = 18083096 | doi = 10.1016/j.cell.2007.11.028 | doi-access = free }}</ref> Under certain conditions, the intracellular Ca²⁺ concentration may begin to oscillate at a specific frequency.<ref name="pmid10864327">{{cite journal | vauthors = Uhlén P, Laestadius A, Jahnukainen T, Söderblom T, Bäckhed F, Celsi G, Brismar H, Normark S, Aperia A, Richter-Dahlfors A | title = Alpha-haemolysin of uropathogenic E. coli induces Ca2+ oscillations in renal epithelial cells | journal = Nature | volume = 405 | issue = 6787 | pages = 694–7 | date = June 2000 | pmid = 10864327 | doi = 10.1038/35015091 | bibcode = 2000Natur.405..694U }}</ref>

=== Phospholipase C pathway === thumb|287x287px|Phospholipase C cleaving PIP2 into IP3 and DAG Specific signals can trigger a sudden increase in the cytoplasmic Ca²⁺ levels to 500–1,000 nM by opening channels in the ER or the plasma membrane. The most common signaling pathway that increases cytoplasmic calcium concentration is the phospholipase C (PLC) pathway.

# Many cell surface receptors, including G protein-coupled receptors and receptor tyrosine kinases, activate the PLC enzyme. # PLC uses the hydrolysis of the membrane phospholipid PIP₂ to form IP₃ and diacylglycerol (DAG), two classic secondary messengers. # DAG attaches to the plasma membrane and recruits protein kinase C (PKC). # Meanwhile, IP₃ diffuses to the ER and is bound to the IP3 receptor. # The IP₃ receptor serves as a Ca²⁺ channel, and releases Ca²⁺ from the ER. # Ca²⁺ binds to PKC and other proteins and activates them.<ref>{{Cite book|title = Essential Cell Biology|publisher = Garland Science|year = 2014|isbn = 978-0-8153-4454-4|location = New York, NY|pages = 548–549 | vauthors = Alberts B, Bray D, Hopkin K, Johnson A, Lewis J, Raff MC, Roberts K, Walter P | display-authors = 6 |edition = 4th}}</ref>

=== Depletion from the endoplasmic reticulum === Depletion of Ca²⁺ from the ER will lead to Ca²⁺ entry from outside the cell by activation of "Store-Operated Channels" (SOCs).<ref name=":0">{{cite journal | vauthors = Putney JW, Tomita T | title = Phospholipase C signaling and calcium influx | journal = Advances in Biological Regulation | volume = 52 | issue = 1 | pages = 152–64 | date = January 2012 | pmid = 21933679 | pmc = 3560308 | doi = 10.1016/j.advenzreg.2011.09.005 }}</ref> This inflow of Ca²⁺ is referred to as Ca²⁺-release-activated Ca²⁺ current (ICRAC). The mechanisms through which ICRAC occurs are currently still under investigation. Although Orai1 and STIM1, have been linked by several studies, for a proposed model of store-operated calcium influx. Recent studies have cited the phospholipase A2 beta,<ref>{{cite journal |last1=Csutora |first1=Peter |last2=Zarayskiy |first2=Vladislav |last3=Peter |first3=Krisztina |last4=Monje |first4=Francisco |last5=Smani |first5=Tarik |last6=Zakharov |first6=Sergey I. |last7=Litvinov |first7=Dmitry |last8=Bolotina |first8=Victoria M. |title=Activation Mechanism for CRAC Current and Store-operated Ca2+ Entry |journal=Journal of Biological Chemistry |date=November 2006 |volume=281 |issue=46 |pages=34926–34935 |doi=10.1074/jbc.M606504200 |pmid=17003039 |doi-access=free }}</ref> nicotinic acid adenine dinucleotide phosphate (NAADP),<ref>{{cite journal | vauthors = Moccia F, Lim D, Nusco GA, Ercolano E, Santella L | title = NAADP activates a Ca2+ current that is dependent on F-actin cytoskeleton | journal = FASEB Journal | volume = 17 | issue = 13 | pages = 1907–9 | date = October 2003 | pmid = 12923070 | doi = 10.1096/fj.03-0178fje | doi-access = free }}</ref> and the protein STIM 1<ref>{{cite journal | vauthors = Baba Y, Hayashi K, Fujii Y, Mizushima A, Watarai H, Wakamori M, Numaga T, Mori Y, Iino M, Hikida M, Kurosaki T | display-authors = 6 | title = Coupling of STIM1 to store-operated Ca2+ entry through its constitutive and inducible movement in the endoplasmic reticulum | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 45 | pages = 16704–9 | date = November 2006 | pmid = 17075073 | pmc = 1636519 | doi = 10.1073/pnas.0608358103 | bibcode = 2006PNAS..10316704B | doi-access = free }}</ref> as possible mediators of ICRAC.

== Role as a Second Messenger == Calcium is a ubiquitous second messenger with wide-ranging physiological roles.<ref name="Demaurex_2016" /> These include muscle contraction, neuronal transmission (as in an excitatory synapse), cellular motility (including the movement of flagella and cilia), fertilization, cell growth (proliferation), neurogenesis, learning and memory as with synaptic plasticity, and secretion of saliva.<ref>{{cite journal |vauthors=Rash BG, Ackman JB, Rakic P |date=February 2016 |title=Bidirectional radial Ca(2+) activity regulates neurogenesis and migration during early cortical column formation |journal=Science Advances |volume=2 |issue=2 |article-number=e1501733 |bibcode=2016SciA....2E1733R |doi=10.1126/sciadv.1501733 |pmc=4771444 |pmid=26933693}}</ref><ref>{{cite journal |vauthors=Berridge MJ, Lipp P, Bootman MD |date=October 2000 |title=The versatility and universality of calcium signalling |journal=Nature Reviews. Molecular Cell Biology |volume=1 |issue=1 |pages=11–21 |doi=10.1038/35036035 |pmid=11413485}}</ref> High levels of cytoplasmic Ca²⁺ can also cause the cell to undergo apoptosis.<ref>{{cite journal |vauthors=Joseph SK, Hajnóczky G |date=May 2007 |title=IP3 receptors in cell survival and apoptosis: Ca2+ release and beyond |journal=Apoptosis |volume=12 |issue=5 |pages=951–68 |doi=10.1007/s10495-007-0719-7 |pmid=17294082 |doi-access=free}}</ref> Other biochemical roles of calcium include regulating enzyme activity, permeability of ion channels,<ref>{{cite journal |vauthors=Ali ES, Hua J, Wilson CH, Tallis GA, Zhou FH, Rychkov GY, Barritt GJ |date=September 2016 |title=The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca(2+) signalling in steatotic hepatocytes |journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research |volume=1863 |issue=9 |pages=2135–46 |doi=10.1016/j.bbamcr.2016.05.006 |pmid=27178543 |doi-access=free}}</ref> activity of ion pumps, and components of the cytoskeleton.<ref>{{cite book |title=Color Atlas of Biochemistry |vauthors=Koolman J, Röhm KH |publisher=Thieme |year=2005 |isbn=978-1-58890-247-4 |location=New York}}{{page needed|date=February 2025}}</ref>

Many of Ca²⁺ mediated events occur when the released Ca²⁺ binds to and activates the regulatory protein calmodulin. Calmodulin may activate the Ca²⁺-calmodulin-dependent protein kinases, or may act directly on other effector proteins.<ref>{{Cite book |title=Biochemistry |vauthors=Berg J, Tymoczko JL, Gatto GJ, Stryer L |edition=Eighth}}</ref> Besides calmodulin, there are many other Ca²⁺-binding proteins that mediate the biological effects of Ca²⁺.

=== In muscle contraction === thumb|342x342px|Comparison of smooth muscle and skeletal muscle contraction Contractions of skeletal muscle fiber are caused due to electrical stimulation. This process is caused by the depolarization of the transverse tubular junctions. Once depolarized the sarcoplasmic reticulum (SR) releases Ca²⁺ into the myoplasm where it will bind to a number of calcium sensitive buffers. The Ca²⁺ in the myoplasm will diffuse to Ca²⁺ regulator sites on the thin filaments. This leads to the actual contraction of the muscle.<ref>{{cite journal | vauthors = Baylor SM, Hollingworth S | title = Calcium indicators and calcium signalling in skeletal muscle fibres during excitation-contraction coupling | journal = Progress in Biophysics and Molecular Biology | volume = 105 | issue = 3 | pages = 162–79 | date = May 2011 | pmid = 20599552 | pmc = 2974769 | doi = 10.1016/j.pbiomolbio.2010.06.001 }}</ref>

Contractions of smooth muscle fiber are dependent on how a Ca²⁺ influx occurs. When a Ca²⁺ influx occurs, cross bridges form between myosin and actin leading to the contraction of the muscle fibers. Influxes may occur from extracellular Ca²⁺ diffusion via ion channels. This can lead to three different results. The first is a uniform increase in the Ca²⁺ concentration throughout the cell. This is responsible for increases in vascular diameters. The second is a rapid time dependent change in the membrane potential which leads to a very quick and uniform increase of Ca²⁺. This can cause a spontaneous release of neurotransmitters via sympathetic or parasympathetic nerve channels. The last potential result is a specific and localized subplasmalemmal Ca²⁺ release. This type of release increases the activation of protein kinase, and is seen in cardiac muscle where it causes excitation-concentration coupling. Ca²⁺ may also result from internal stores found in the SR. This release may be caused by Ryaodine (RYRs) or IP₃ receptors. RYRs Ca²⁺ release is spontaneous and localized. This has been observed in a number of smooth muscle tissues including arteries, portal vein, urinary bladder, ureter tissues, airway tissues, and gastrointestinal tissues. IP₃ Ca²⁺ release is caused by activation of the IP₃ receptor on the SR. These influxes are often spontaneous and localized as seen in the colon and portal vein, but may lead to a global Ca²⁺ wave as observed in many vascular tissues.<ref>{{cite journal | vauthors = Hill-Eubanks DC, Werner ME, Heppner TJ, Nelson MT | title = Calcium signaling in smooth muscle | journal = Cold Spring Harbor Perspectives in Biology | volume = 3 | issue = 9 | article-number = a004549 | date = September 2011 | pmid = 21709182 | pmc = 3181028 | doi = 10.1101/cshperspect.a004549 }}</ref>

=== In neurons === In neurons, concurrent increases of cytosolic and mitochondrial Ca²⁺ are important to synchronize the electrical activity of a neuron with its mitochondrial energy metabolism. The calcium levels of the mitochondrial matrix need to stay around 10-30 μM to activate isocitrate dehydrogenase, which is one of the key regulatory enzymes of the Krebs cycle.<ref>{{cite journal | vauthors = Ivannikov MV, Macleod GT | title = Mitochondrial free Ca²⁺ levels and their effects on energy metabolism in Drosophila motor nerve terminals | journal = Biophysical Journal | volume = 104 | issue = 11 | pages = 2353–61 | date = June 2013 | pmid = 23746507 | pmc = 3672877 | doi = 10.1016/j.bpj.2013.03.064 | bibcode = 2013BpJ...104.2353I }}</ref><ref>{{cite journal | vauthors = Ivannikov MV, Sugimori M, Llinás RR | title = Synaptic vesicle exocytosis in hippocampal synaptosomes correlates directly with total mitochondrial volume | journal = Journal of Molecular Neuroscience | volume = 49 | issue = 1 | pages = 223–30 | date = January 2013 | pmid = 22772899 | pmc = 3488359 | doi = 10.1007/s12031-012-9848-8 }}</ref>

The Endoplasmic Reticulum (ER), in neurons, may serve in a network integrating numerous extracellular and intracellular signals in a binary membrane system with the plasma membrane. Such an association with the plasma membrane creates the relatively new perception of the ER and theme of "a neuron within a neuron."<ref>{{Cite journal |last1=Öztürk |first1=Zeynep |last2=O'Kane |first2=Cahir J. |last3=Pérez-Moreno |first3=Juan José |date=2020-01-29 |title=Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration |journal=Frontiers in Neuroscience |language=English |volume=14 |article-number=48 |doi=10.3389/fnins.2020.00048 |doi-access=free |pmid=32116502 |pmc=7025499 |issn=1662-453X}}</ref> The ER's structural characteristics, including its ability to act as a Ca²⁺ store and use specific Ca²⁺ releasing proteins, serve to create a system that may release regenerative waves of Ca²⁺ which balance cytosolic Ca²⁺ levels. These networks may communicate both locally and globally in the cell. Ca²⁺ signals are integrated through extracellular and intracellular fluxes, and have been implicated to play roles in synaptic plasticity, memory, neurotransmitter release, neuronal excitability, and long term changes at the gene transcription level. Ca²⁺ signaling is also related to ER stress. Along with the unfolded protein response, improper signaling pathways can cause ER associated degradation (ERAD) and autophagy.<ref>{{cite journal | vauthors = Berridge MJ | title = Neuronal calcium signaling | journal = Neuron | volume = 21 | issue = 1 | pages = 13–26 | date = July 1998 | pmid = 9697848 | doi = 10.1016/S0896-6273(00)80510-3 | doi-access = free }}</ref>

One key Ca²⁺ signaling pathway in neurons involves the release of neurotransmitters. When an action potential reaches the end of a neuron, voltage-gated calcium channels open. This allows Ca²⁺ to enter the neuron locally and interact with synaptotagmin and other SNARE proteins. These proteins sense the spikes in Ca²⁺ levels and trigger the release of synaptic vesicles which deposit neurotransmitters into the synapse.

Astrocytes have a direct relationship with neurons through them releasing gliotransmitters. These transmitters allow communication between neurons and are triggered by calcium levels increasing around astrocytes from inside stores. This increase in calcium can also be caused by other neurotransmitters. Some examples of gliotransmitters are ATP and glutamate.<ref>{{Cite journal |last1=Harada |first1=Kazuki |last2=Kamiya |first2=Taichi |last3=Tsuboi |first3=Takashi |date=2016-01-12 |title=Gliotransmitter release from astrocytes: functional, developmental and pathological implications in the brain |journal=Frontiers in Neuroscience |language=English |volume=9 |page=499 |doi=10.3389/fnins.2015.00499 |doi-access=free |pmid=26793048 |issn=1662-453X|pmc=4709856 }}</ref> Activation of these neurons will lead to a 10-fold increase in the concentration of calcium in the cytosol from 100 nanomolar to 1 micromolar.<ref>{{Cite journal |last=Bootman |first=Martin |date=July 4, 2012 |title=Calcium Signaling |journal=Cold Spring Harbor Perspectives in Biology |volume=4 |issue=7 |article-number=a011171 |doi=10.1101/cshperspect.a011171 |pmid=22751152 |pmc=3385957 }}</ref>

=== In fertilization === Ca²⁺ influx during fertilization has been observed in many species as a trigger for development of the oocyte. These influxes may occur as a single increase in concentration as seen with fish and echinoderms, or may occur with the concentrations oscillating as observed in mammals. The triggers to these Ca²⁺ influxes may differ. The influx have been observed to occur via membrane Ca²⁺ conduits and Ca²⁺ stores in the sperm. It has also been seen that sperm binds to membrane receptors that lead to a release in Ca²⁺ from the ER. The sperm has also been observed to release a soluble factor that is specific to that species. This prevents cross species fertilization to occur. These soluble factors lead to activation of IP₃ which causes a Ca²⁺ release from the ER via IP₃ receptors.<ref>{{cite journal | vauthors = Kashir J, Deguchi R, Jones C, Coward K, Stricker SA | title = Comparative biology of sperm factors and fertilization-induced calcium signals across the animal kingdom | journal = Molecular Reproduction and Development | volume = 80 | issue = 10 | pages = 787–815 | date = October 2013 | pmid = 23900730 | doi = 10.1002/mrd.22222 | doi-access = free }}</ref> It has also been seen that some model systems mix these methods such as seen with mammals.<ref>{{cite journal | vauthors = Ohto U, Ishida H, Krayukhina E, Uchiyama S, Inoue N, Shimizu T | title = Structure of IZUMO1-JUNO reveals sperm-oocyte recognition during mammalian fertilization | journal = Nature | volume = 534 | issue = 7608 | pages = 566–9 | date = June 2016 | pmid = 27309808 | doi = 10.1038/nature18596 | bibcode = 2016Natur.534..566O }}</ref><ref>{{cite journal | vauthors = Swann K, Lai FA | title = Egg Activation at Fertilization by a Soluble Sperm Protein | journal = Physiological Reviews | volume = 96 | issue = 1 | pages = 127–49 | date = January 2016 | pmid = 26631595 | doi = 10.1152/physrev.00012.2015 }}</ref> Once the Ca²⁺ is released from the ER the egg starts the process of forming a fused pronucleus and the restart of the mitotic cell cycle.<ref>{{Cite book|last=Gilbert, Scott F., 1949-|title=Developmental biology|others=Barresi, Michael J. F., 1974-|isbn=978-1-60535-470-5|edition=Eleventh|location=Sunderland, Massachusetts|page=221|oclc=945169933|date=2016-06-15}}</ref> Ca²⁺ release is also responsible for the activation of NAD⁺ kinase which leads to membrane biosynthesis, and the exocytosis of the oocytes cortical granules which leads to the formation of the hyaline layer allowing for the slow block to polyspermy.

=== Cell Proliferation === Ca²⁺ plays a significant role in cellular proliferation in mammalian cells.<ref name=":1">{{Cite journal |last1=Kahl |first1=Christina R. |last2=Means |first2=Anthony R. |date=December 1, 2003 |title=Regulation of cell cycle progression by calcium/calmodulin-dependent pathways |journal=Endocrine Reviews |volume=24 |issue=6 |pages=719–736 |doi=10.1210/er.2003-0008 |issn=0163-769X |pmid=14671000}}</ref> The complete mechanism on how Ca²⁺ regulates progression of the cell cycle is not yet fully established. However, research supports the fact that CaM is required for cell cycle progression, especially at the G2 to M phase.<ref name=":1" /> When Ca²⁺ enters the cell through the SOCs, it binds to CaM.<ref name=":0" /> CaM activates calmodulin-dependent protein kinase II (CaMKII), which triggers Cdc25, a phosphatase that removes inhibitory phosphate groups from Cyclin-dependent Kinase 1 (Cdk1).<ref name=":2">{{Cite journal |last1=Patel |first1=Rajnikant |last2=Holt |first2=Mark |last3=Philipova |first3=Rada |last4=Moss |first4=Stephen |last5=Schulman |first5=Howard |last6=Hidaka |first6=Hiroyoshi |last7=Whitaker |first7=Michael |date=1999-03-19 |title=Calcium/Calmodulin-dependent Phosphorylation and Activation of Human Cdc25-C at the G2/M Phase Transition in HeLa Cells* |journal=Journal of Biological Chemistry |volume=274 |issue=12 |pages=7958–7968 |doi=10.1074/jbc.274.12.7958 |doi-access=free|pmid=10075693 |issn=0021-9258}}</ref> This results in the activation of Cdk1, triggering the transition to the mitosis phase of the cell cycle.<ref name=":2" /> Spindle assembly and nuclear breakdown occurs due to the Cdk1-Cyclin B complex.<ref>{{Cite journal |last1=Timofeev |first1=Oleg |last2=Cizmecioglu |first2=Onur |last3=Settele |first3=Florian |last4=Kempf |first4=Tore |last5=Hoffmann |first5=Ingrid |date=2010-05-28 |title=Cdc25 phosphatases are required for timely assembly of CDK1-cyclin B at the G2/M transition |journal=The Journal of Biological Chemistry |volume=285 |issue=22 |pages=16978–16990 |doi=10.1074/jbc.M109.096552 |doi-access=free|issn=1083-351X |pmc=2878026 |pmid=20360007}}</ref>

=== Synaptic Plasticity === thumb|333x333px|Role of Ca2+ as one major messenger in synaptic plasticity Neuroplasticity, the brain's ability to change, create and reorganize neuronal synapses in response to different stimuli and experiences, is driven by Ca²⁺.<ref name=":3">{{Cite journal |last1=Marzola |first1=Patrícia |last2=Melzer |first2=Thayza |last3=Pavesi |first3=Eloisa |last4=Gil-Mohapel |first4=Joana |last5=Brocardo |first5=Patricia S. |date=2023-11-21 |title=Exploring the Role of Neuroplasticity in Development, Aging, and Neurodegeneration |journal=Brain Sciences |volume=13 |issue=12 |page=1610 |doi=10.3390/brainsci13121610 |doi-access=free|issn=2076-3425 |pmc=10741468 |pmid=38137058}}</ref> Neuroplasticity is the key to memory, learning and adaption.<ref name=":3" />

==== Long-Term Potentiation ==== Long-Term Potentiation (LTP) is an increase in synaptic strength or activity, caused by a high influx of Ca²⁺.<ref name=":4">{{Citation |last1=Purves |first1=Dale |title=Long-Term Synaptic Potentiation |date=2001 |work=Neuroscience. 2nd edition |url=https://www.ncbi.nlm.nih.gov/books/NBK10878/ |access-date=2026-03-15 |publisher=Sinauer Associates |language=en |last2=Augustine |first2=George J. |last3=Fitzpatrick |first3=David |last4=Katz |first4=Lawrence C. |last5=LaMantia |first5=Anthony-Samuel |last6=McNamara |first6=James O. |last7=Williams |first7=S. Mark}}</ref> LTP strengthens the connections between neurons and is a vital part of long-term memory.<ref name=":4" /> LTP is divided into 2 phases: Early-phase LTP and Late-phase LTP.

===== Early Phase LTP ===== Early-phase LTP (E-LTP) lasts between 1-3 hours and is triggered by high frequency stimulations, which causes depolarization.<ref>{{Cite journal |last=Huang |first=Emily P |date=1998-05-07 |title=Synaptic plasticity: Going through phases with LTP |url=https://www.sciencedirect.com/science/article/pii/S0960982298702192 |journal=Current Biology |volume=8 |issue=10 |pages=R350–R352 |doi=10.1016/S0960-9822(98)70219-2 |pmid=9601635 |bibcode=1998CBio....8.R350H |issn=0960-9822}}</ref> Ca²⁺ ions enter the post-synaptic neuron through activated NMDA receptors.<ref>{{Cite journal |last1=Lüscher |first1=Christian |last2=Malenka |first2=Robert C. |date=2012-06-01 |title=NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD) |journal=Cold Spring Harbor Perspectives in Biology |volume=4 |issue=6 |article-number=a005710 |doi=10.1101/cshperspect.a005710 |issn=1943-0264 |pmc=3367554 |pmid=22510460}}</ref> 4 Ca²⁺ ions bind to calmodulin (CaM), which exposes its hydrophobic residues and activates the molecule.<ref>{{Cite journal |last1=Rostas |first1=John A. P. |last2=Skelding |first2=Kathryn A. |date=2023-01-23 |title=Calcium/Calmodulin-Stimulated Protein Kinase II (CaMKII): Different Functional Outcomes from Activation, Depending on the Cellular Microenvironment |journal=Cells |volume=12 |issue=3 |page=401 |doi=10.3390/cells12030401 |doi-access=free|issn=2073-4409 |pmc=9913510 |pmid=36766743}}</ref> CaM binds to calmodulin-dependent protein kinase II (CaMKII),<ref>{{Cite journal |last=Byth |first=Lachlan A. |date=October 2014 |title=Ca(2+)- and CaMKII-mediated processes in early LTP |journal=Annals of Neurosciences |volume=21 |issue=4 |pages=151–153 |doi=10.5214/ans.0972.7531.210408 |issn=0972-7531 |pmc=4248478 |pmid=25452677}}</ref> which phosphorylates AMPA receptors at its Glu-A1 subunit.<ref>{{Cite journal |last=Byth |first=Lachlan A. |date=October 2014 |title=Ca(2+)- and CaMKII-mediated processes in early LTP |journal=Annals of Neurosciences |volume=21 |issue=4 |pages=151–153 |doi=10.5214/ans.0972.7531.210408 |issn=0972-7531 |pmc=4248478 |pmid=25452677}}</ref> This results in the insertion of more AMPA receptors in the post-synaptic membrane, and an increase in AMPA activity.<ref>{{Cite journal |last1=Chater |first1=Thomas E. |last2=Goda |first2=Yukiko |date=2014 |title=The role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity |journal=Frontiers in Cellular Neuroscience |volume=8 |page=401 |doi=10.3389/fncel.2014.00401 |doi-access=free|issn=1662-5102 |pmc=4245900 |pmid=25505875}}</ref> Post-synaptic neurons generate stronger synaptic responses and transmission to a given amount of glutamate released from the presynaptic neuron (which is needed to activate NMDA).<ref>{{Cite journal |last1=Wu |first1=Qing-Lin |last2=Gao |first2=Yan |last3=Li |first3=Jun-Tong |last4=Ma |first4=Wen-Yu |last5=Chen |first5=Nai-Hong |date=August 26, 2021 |title=The Role of AMPARs Composition and Trafficking in Synaptic Plasticity and Diseases |journal=Cellular and Molecular Neurobiology |volume=42 |issue=8 |pages=2489–2504 |doi=10.1007/s10571-021-01141-z |issn=1573-6830 |pmc=11421597 |pmid=34436728}}</ref>

===== Late Phase LTP ===== Late-phase LTP occurs a few hours after the stimulus, and lasts from a few hours to a couple of days.<ref>{{Cite journal |last1=Cao |first1=Guan |last2=Harris |first2=Kristen M. |date=February 2012 |title=Developmental regulation of the late phase of long-term potentiation (L-LTP) and metaplasticity in hippocampal area CA1 of the rat |journal=Journal of Neurophysiology |volume=107 |issue=3 |pages=902–912 |doi=10.1152/jn.00780.2011 |issn=1522-1598 |pmc=3289468 |pmid=22114158}}</ref> Repeated stimulation causes a rise in Ca²⁺ levels, activating adenylyl cyclase (AC).<ref name=":5">{{Citation |last1=Duman |first1=Ronald S. |title=Adenylyl Cyclases |date=1999 |work=Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition |url=https://www.ncbi.nlm.nih.gov/books/NBK27958/ |access-date=2026-03-15 |publisher=Lippincott-Raven |language=en |last2=Nestler |first2=Eric J.}}</ref> AC converts ATP into cAMP;<ref name=":5" /> An increase in cAMP levels causes it to bind to the regulatory subunits of Protein Kinase A (PKA), changing its conformation and activating it.<ref>{{Cite journal |last=Sassone-Corsi |first=Paolo |date=2012-12-01 |title=The cyclic AMP pathway |journal=Cold Spring Harbor Perspectives in Biology |volume=4 |issue=12 |article-number=a011148 |doi=10.1101/cshperspect.a011148 |issn=1943-0264 |pmc=3504441 |pmid=23209152}}</ref> PKA phosphorylates cAMP response element-binding protein (CREB) at the Ser-133 residue, inside the nucleus<ref>{{Cite journal |last=Kida |first=Satoshi |date=December 26, 2012 |title=A Functional Role for CREB as a Positive Regulator of Memory Formation and LTP |journal=Experimental Neurobiology |volume=21 |issue=4 |pages=136–140 |doi=10.5607/en.2012.21.4.136 |issn=1226-2560 |pmc=3538177 |pmid=23319873}}</ref>.Then, CREB binds to DNA at the CRE sequences, promoting transcription and protein synthesis, and the creation of new AMPA receptors in the plasma membrane for long-lasting synaptic changes.<ref>{{Cite journal |last1=Abel |first1=Ted |last2=Nguyen |first2=Peter V |last3=Barad |first3=Mark |last4=Deuel |first4=Thomas A. S |last5=Kandel |first5=Eric R |last6=Bourtchouladze |first6=Roussoudan |date=1997-03-07 |title=Genetic Demonstration of a Role for PKA in the Late Phase of LTP and in Hippocampus-Based Long-Term Memory |url=https://www.sciencedirect.com/science/article/pii/S0092867400819042 |journal=Cell |volume=88 |issue=5 |pages=615–626 |doi=10.1016/S0092-8674(00)81904-2 |pmid=9054501 |issn=0092-8674}}</ref><ref>{{Cite journal |title=Ryanodine receptors contribute to cGMP-induced late-phase LTP and CREB phosphorylation in the hippocampus |language=en |doi=10.1152/jn.2002.88.3.1270|date=September 2002|last=Lu|first=Yun-Fei |journal=Journal of Neurophysiology |volume=88 |issue=3 |pages=1270–1278 |pmid=12205148 }}</ref>

==== Long-Term Depression ==== Long-term Depression (LTD) is the decrease in synaptic strength and activity, caused by a low influx of Ca²⁺.<ref name=":6">{{Cite journal |last1=Piochon |first1=Claire |last2=Kano |first2=Masanobu |last3=Hansel |first3=Christian |date=2016-09-27 |title=LTD-like molecular pathways in developmental synaptic pruning |journal=Nature Neuroscience |volume=19 |issue=10 |pages=1299–1310 |doi=10.1038/nn.4389 |issn=1546-1726 |pmc=5070480 |pmid=27669991}}</ref> LTD weakens the connection between neurons, removing unnecessary circuits and old memories, providing a balance to LTP.<ref name=":6" />

Low frequency stimulation causes a low, prolonged rise in Ca²⁺ levels in the post-synaptic cell.<ref>{{Cite journal |last1=Yang |first1=S. N. |last2=Tang |first2=Y. G. |last3=Zucker |first3=R. S. |date=February 1999 |title=Selective induction of LTP and LTD by postsynaptic [Ca2+]i elevation |journal=Journal of Neurophysiology |volume=81 |issue=2 |pages=781–787 |doi=10.1152/jn.1999.81.2.781 |issn=0022-3077 |pmid=10036277}}</ref> Calcineurin, a protein phosphatase, has a higher affinity for Ca²⁺ then CaMKII does, so calcineurin is activated in low levels of Ca²⁺ present.<ref>{{Cite journal |last1=Lüscher |first1=Christian |last2=Malenka |first2=Robert C. |date=2012-06-01 |title=NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD) |journal=Cold Spring Harbor Perspectives in Biology |volume=4 |issue=6 |article-number=a005710 |doi=10.1101/cshperspect.a005710 |issn=1943-0264 |pmc=3367554 |pmid=22510460}}</ref> Calcineurin dephosphorylates AMPA, especially at Ser-845 residue on the Glu-A1 subunit<ref>{{Cite journal |last1=Sathler |first1=Matheus F. |last2=Khatri |first2=Latika |last3=Roberts |first3=Jessica P. |last4=Schmidt |first4=Isabella G. |last5=Zaytseva |first5=Anastasiya |last6=Kubrusly |first6=Regina C. C. |last7=Ziff |first7=Edward B. |last8=Kim |first8=Seonil |date=2021-09-01 |title=Phosphorylation of the AMPA receptor subunit GluA1 regulates clathrin-mediated receptor internalization |journal=Journal of Cell Science |volume=134 |issue=17 |pages=jcs257972 |doi=10.1242/jcs.257972 |issn=1477-9137 |pmc=8445600 |pmid=34369573}}</ref>.This results in the removal of AMPA receptors from the membrane via the ligase NEDD4-1, weaking the overall synapse.<ref>{{Cite journal |last1=Widagdo |first1=Jocelyn |last2=Guntupalli |first2=Sumasri |last3=Jang |first3=Se E. |last4=Anggono |first4=Victor |date=2017-10-26 |title=Regulation of AMPA Receptor Trafficking by Protein Ubiquitination |journal=Frontiers in Molecular Neuroscience |language=English |volume=10 |article-number=347 |doi=10.3389/fnmol.2017.00347 |doi-access=free|pmid=29123470 |pmc=5662755 |issn=1662-5099}}</ref><ref>{{Cite journal |last1=Lanté |first1=Fabien |last2=Toledo-Salas |first2=Juan-Carlos |last3=Ondrejcak |first3=Tomas |last4=Rowan |first4=Michael J. |last5=Ulrich |first5=Daniel |date=2011-03-16 |title=Removal of synaptic Ca²+-permeable AMPA receptors during sleep |journal=The Journal of Neuroscience: The Official Journal of the Society for Neuroscience |volume=31 |issue=11 |pages=3953–3961 |doi=10.1523/JNEUROSCI.3210-10.2011 |issn=1529-2401 |pmc=6623525 |pmid=21411638}}</ref>

=== Cell Apoptosis === Increased intracellular level of Ca²⁺ can be a trigger for apoptosis by activating several molecules that release cytochrome c and other death signals.<ref>{{Cite journal |last1=Afford |first1=S. |last2=Randhawa |first2=S. |date=April 2000 |title=Apoptosis |journal=Molecular Pathology: MP |volume=53 |issue=2 |pages=55–63 |doi=10.1136/mp.53.2.55 |issn=1366-8714 |pmc=1186906 |pmid=10889903}}</ref> One of these pathways occurs when excessive Ca²⁺ in the cytoplasm is taken up by the mitochondrial matrix. High levels of Ca²⁺ in the matrix causes the mitochondrial permeability transition pores (mPTP) to open.<ref>{{Cite journal |last1=Baumgartner |first1=Heidi K. |last2=Gerasimenko |first2=Julia V. |last3=Thorne |first3=Christopher |last4=Ferdek |first4=Pawel |last5=Pozzan |first5=Tullio |last6=Tepikin |first6=Alexei V. |last7=Petersen |first7=Ole H. |last8=Sutton |first8=Robert |last9=Watson |first9=Alastair J. M. |last10=Gerasimenko |first10=Oleg V. |date=2009-07-31 |title=Calcium elevation in mitochondria is the main Ca2+ requirement for mitochondrial permeability transition pore (mPTP) opening |journal=The Journal of Biological Chemistry |volume=284 |issue=31 |pages=20796–20803 |doi=10.1074/jbc.M109.025353 |doi-access=free|issn=1083-351X |pmc=2742844 |pmid=19515844}}</ref> This causes a huge influx of solutes and water into the mitochondrial membrane, causing it to expand and rupture.<ref>{{Cite journal |last1=Kwong |first1=Jennifer Q. |last2=Molkentin |first2=Jeffery D. |date=2015-02-03 |title=Physiological and pathological roles of the mitochondrial permeability transition pore in the heart |journal=Cell Metabolism |volume=21 |issue=2 |pages=206–214 |doi=10.1016/j.cmet.2014.12.001 |issn=1932-7420 |pmc=4616258 |pmid=25651175}}</ref> This rupturing of the membrane releases cytochrome c, a molecule in the mitochondria that triggers apoptosis.<ref>{{Cite journal |last1=Hüttemann |first1=Maik |last2=Pecina |first2=Petr |last3=Rainbolt |first3=Matthew |last4=Sanderson |first4=Thomas H. |last5=Kagan |first5=Valerian E. |last6=Samavati |first6=Lobelia |last7=Doan |first7=Jeffrey W. |last8=Lee |first8=Icksoo |date=May 2011 |title=The multiple functions of cytochrome c and their regulation in life and death decisions of the mammalian cell: From respiration to apoptosis |journal=Mitochondrion |volume=11 |issue=3 |pages=369–381 |doi=10.1016/j.mito.2011.01.010 |issn=1872-8278 |pmc=3075374 |pmid=21296189}}</ref> In the cytoplasm, cytochrome c binds to Apoptotic Protease-Activating Factor-1 (APAF-1), triggering oligomerization into an apoptosome.<ref>{{Cite journal |last1=Bratton |first1=S. B. |last2=Walker |first2=G. |last3=Srinivasula |first3=S. M. |last4=Sun |first4=X. M. |last5=Butterworth |first5=M. |last6=Alnemri |first6=E. S. |last7=Cohen |first7=G. M. |date=2001-03-01 |title=Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes |journal=The EMBO Journal |volume=20 |issue=5 |pages=998–1009 |doi=10.1093/emboj/20.5.998 |issn=0261-4189 |pmc=145489 |pmid=11230124}}</ref><ref name=":7">{{Cite journal |last1=Bratton |first1=Shawn B. |last2=Salvesen |first2=Guy S. |date=2010-10-01 |title=Regulation of the Apaf-1-caspase-9 apoptosome |journal=Journal of Cell Science |volume=123 |issue=Pt 19 |pages=3209–3214 |doi=10.1242/jcs.073643 |issn=1477-9137 |pmc=2939798 |pmid=20844150}}</ref> This results in the recruitment of procaspace-9, which activates caspace-3, the primary caspase that starts apoptosis by triggering proteins that lead to cellular destruction.

=== See also === *Nanodomain *European Calcium Society

== References == {{Reflist|33em}}

== Further reading == * {{cite journal | vauthors = Petersen OH | title = Ca2+ signalling and Ca2+-activated ion channels in exocrine acinar cells | journal = Cell Calcium | volume = 38 | issue = 3–4 | pages = 171–200 | year = 2005 | pmid = 16107275 | doi = 10.1016/j.ceca.2005.06.024 }}

{{Commons category}}

{{Cell signaling}} {{Calcium signaling}}

{{DEFAULTSORT:Calcium Signaling}} Category:Cell signaling Category:Signal transduction Category:Calcium signaling