Neuronal calcium sensor-1

NCS-1 regulates synaptic transmission,{{cite journal | vauthors = Dason JS, Romero-Pozuelo J, Marin L, Iyengar BG, Klose MK, Ferrus A, Atwood HL | title = Frequenin/NCS-1 and the Ca2+-channel {alpha}1-subunit co-regulate synaptic transmission and nerve-terminal growth. | journal = Journal of Cell Science | volume = 122 | issue = 22 | pages = 4109–4121 | year = 2009 | pmid = 19861494 | doi = 10.1242/jcs.055095 | s2cid = 2663472 | doi-access = }} helps control the dynamics of nerve terminal growth,{{cite journal | vauthors = Romero-Pozuelo J, Dason JS, Atwood HL, Ferrus A | title = Chronic and acute alterations in the functional levels of Frequenins 1 and 2 reveal their roles in synaptic transmission and axon terminal morphology. | journal = European Journal of Neuroscience | volume = 26 | issue = 9 | pages = 2428–2443 | year = 2007 | pmid = 17970740 | doi = 10.1111/j.1460-9568.2007.05877.x | hdl = 10261/72998 | s2cid = 11989516 | hdl-access = free }}{{cite journal | vauthors = Hui K, Fei GH, Saab BJ, Su J, Roder JC, Feng ZP | title = Neuronal calcium sensor-1 modulation of optimal calcium level for neurite outgrowth. | journal = Development | volume = 134 | issue = 24 | pages = 4479–4489 | year = 2007 | pmid = 18039973 | doi=10.1242/dev.008979| doi-access = free }}{{cite journal | vauthors = Dason JS, Romero-Pozuelo J, Marin L, Iyengar BG, Klose MK, Ferrus A, Atwood HL | title = Frequenin/NCS-1 and the Ca2+-channel {alpha}1-subunit co-regulate synaptic transmission and nerve-terminal growth. | journal = Journal of Cell Science | volume = 122 | issue = 22 | pages = 4109–4121 | year = 2009 | pmid = 19861494 | doi = 10.1242/jcs.055095 | s2cid = 2663472 | doi-access = }} is critical for some forms of learning and memory in C. elegans{{cite journal | vauthors = Gomez M, De Castro E, Guarin E, Sasakura H, Kuhara A, Mori I, Bartfai T, Bargmann CI, Nef P | title = Ca2+ signaling via the neuronal calcium sensor-1 regulates associative learning and memory in C. elegans | journal = Neuron | volume = 30 | issue = 1 | pages = 241–8 | year = 2001 | pmid = 11343658 | doi = 10.1016/S0896-6273(01)00276-8 | s2cid = 9413106 | doi-access = free }} and mammals,{{cite journal | vauthors = Saab BJ, Georgiou J, Nath A, Lee FJ, Wang M, Michalon A, Liu F, Mansuy IM, Roder JC | title = NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory | journal = Neuron | volume = 63 | issue = 5 | pages = 643–56 | year = 2009 | pmid = 19755107 | doi = 10.1016/j.neuron.2009.08.014 | s2cid = 5321020 | doi-access = free }} regulates corticohippocampal plasticity; and enhancing levels of NCS-1 in the mouse dentate gyrus increases spontaneous exploration of safe environments, potentially linking NCS-1 to curiosity.{{cite news|last=McDermott|first=Melissa|title=Researchers discover the first-ever link between intelligence and curiosity|url=http://phys.org/news172174436.html|access-date=21 September 2012|newspaper=PHYS ORG|date=September 14, 2009}}

NCS-1 is a calcium sensor, not a calcium buffer (chelator); thus it is a high-affinity, low-capacity, calcium-binding protein.

Frq can substitute for calmodulin in some situations. It is thought to be associated with neuronal secretory vesicles and regulate neurosecretion.

1. It is the Ca²⁺-sensing subunit of the yeast phosphatidylinositol (PtdIns)-4-OH kinase, PIK1
2. It binds to many proteins, some in calcium dependent and some in calcium independent ways, and switches many of the targets "on" (some off).
3. Calcineurin (protein phosphatase 2B)
4. GRK2 (G-protein-coupled receptor kinase 2)
5. D₂ dopamine receptor
6. IL1RAPL1 (interleukin-1 receptor accessory protein-like 1 protein)
7. PI4KIIIβ (type III phosphatidylinositol 4-kinase β)
8. IP3 receptor (this activity is inhibited by lithium - a drug used for the treatment of bipolar disorder){{cite journal | vauthors = Schlecker C, Boehmerle W, Jeromin A, DeGray B, Varshney A, Sharma Y, Szigeti-Buck K, Ehrlich BE | title = Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium | journal = J. Clin. Invest. | volume = 116 | issue = 6 | pages = 1668–74 | year = 2006 | pmid = 16691292 | doi = 10.1172/JCI22466 | pmc = 1459068 }}
9. 3',5'-cyclic nucleotide phosphodiesterases
10. ARF1 (ADP Ribosylation factor 1)
11. A type (K_v4.3; Shal-related subfamily, member 3) voltage-gated potassium channels
12. Nitric oxide synthase
13. TRPC5 channel{{cite journal | vauthors = Hui H, McHugh D, Hannan M, Zeng F, Xu SZ, Khan SU, Levenson R, Beech DJ, Weiss JL | title = Calcium-sensing mechanism in TRPC5 channels contributing to retardation of neurite outgrowth | journal = J. Physiol. | volume = 572 | issue = Pt 1 | pages = 165–72 |date=April 2006 | pmid = 16469785 | pmc = 1779652 | doi = 10.1113/jphysiol.2005.102889 }}
14. Ric8a{{cite journal | vauthors = Romero-Pozuelo J, Dason JS, Mansilla A, Baños-Mateos S, Sardina JL, Chaves-Sanjuán A, Jurado-Gómez J, Santana E, Atwood HL, Hernández-Hernández A, Sánchez-Barrena MJ, Ferrús A | title = The guanine-exchange factor Ric8a binds to the Ca2+ sensor NCS-1 to regulate synapse number and neurotransmitter release. | journal = Journal of Cell Science | volume = 127 | issue = 19 | pages = 4246–4259 | year = 2014 | pmid = 25074811 | doi = 10.1242/jcs.152603 | doi-access = free | hdl = 10261/167910 | hdl-access = free }}
15. Frq modulates Ca²⁺ entry through a functional interaction with the α₁ voltage-gated Ca²⁺-channel subunit.

NCS-1 is a globular protein consisting of ten alpha-helices. Four pairs of alpha-helices each form independent 12-amino-acid loops containing a negatively charged calcium binding domain known as an EF-hand. However, only three of these EF hands are functional (the most N-terminal EF-hand does not bind calcium). They could be occupied not only by calcium but also by magnesium and zinc ions.{{cite journal | vauthors = Tsvetkov PO, Roman AY, Baksheeva VE, Nazipova AA, Shevelyova MP, Vladimirov VI, Buyanova MF, Zinchenko DV, Zamyatnin AA, Devred F, Golovin AV, Permyakov SE, Zernii EY | title = Functional Status of Neuronal Calcium Sensor-1 Is Modulated by Zinc Binding | journal = Frontiers in Molecular Neuroscience | volume = 11 | pages = 459 | date = 2018 | pmid = 30618610 | doi = 10.3389/fnmol.2018.00459 | url = https://hal-amu.archives-ouvertes.fr/hal-01955226/file/fnmol-11-00459.pdf | pmc=6302015| doi-access = free }} NCS-1 also contains at least two known protein binding domains, and a large surface exposed hydrophobic crevice containing EF-hands three and four. There is a myristoylation motif at the N-terminus that presumably allows NCS-1 to associate with lipid membranes.

The expression of NCS-1 increases in bipolar disorder and some forms of schizophrenia{{cite journal | vauthors = Koh PO, Undie AS, Kabbani N, Levenson R, Goldman-Rakic PS, Lidow MS | title = Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients | journal = Proc Natl Acad Sci U S A | volume = 100 | issue = 1 | pages = 313–7 | pmid = 12496348 | doi = 10.1073/pnas.232693499 | year = 2003 | pmc = 140961 | bibcode = 2003PNAS..100..313K | doi-access = free }} and decreases in inflammatory bowel disease.{{cite journal | vauthors = Lourenssen S, Jeromin A, Roder J, Blennerhassett MG | title = Intestinal inflammation modulates expression of the synaptic vesicle protein neuronal calcium sensor-1 | journal = Am. J. Physiol. Gastrointest. Liver Physiol. | volume = 282 | issue = 6 | pages = G1097–104 | year = 2002 | pmid = 12016136 | doi = 10.1152/ajpgi.00320.2001 | s2cid = 42387548 }} A mutant of NCS-1, R102Q, has also been found in one patient with Autism.{{cite journal | vauthors = Handley MT, Lian LY, Haynes LP, Burgoyne RD | title = Structural and functional deficits in a neuronal calcium sensor-1 mutant identified in a case of autistic spectrum disorder | journal = PLOS ONE | volume = 5 | issue = 5 | pages = e10534 | year = 2010 | pmid = 20479890 | pmc = 2866544 | doi = 10.1371/journal.pone.0010534 | bibcode = 2010PLoSO...510534H | doi-access = free }} In addition NCS-1 is significant in intelligence in creating curiosity by its function on dopamine D2 receptors in the dentate gyrus, increasing memory for complex tasks.{{cite web |last1=McDermott |first1=Melissa |title=Researchers discover the first-ever link between intelligence and curiosity |url=http://www.physorg.com/news172174436.html |website=medicalxpress.com |access-date=31 January 2024 |language=en}} Interactions of lithium ions (Li+) with NCS-1 has also been linked as a possible treatment for protection against psychotic disorders.{{Cite journal |last1=Alam |first1=Md Shofiul |last2=Cedeño |first2=Jonathan |last3=Reyes |first3=Michael A. |last4=Scavuzzo |first4=Sebastian |last5=Miksovska |first5=Jaroslava |date=January 2025 |title=Interactions of Li+ ions with NCS1: A potential mechanism of Li+ neuroprotective action against psychotic disorders |url=https://www.sciencedirect.com/science/article/abs/pii/S0162013424002873 |journal=Journal of Inorganic Biochemistry |volume=262 |pages=1–10 |doi=10.1016/j.jinorgbio.2024.112762 |pmid=39447483 |via=Elsevier Science Direct}}

NCS-1 was originally discovered in Drosophila as a gain-of-function mutation associated with frequency-dependent increases in neurotransmission.{{cite journal | vauthors = Pongs O, Lindemeier J, Zhu XR, Theil T, Engelkamp D, Krah-Jentgens I, Lambrecht HG, Koch KW, Schwemer J, Rivosecchi R, Mallart A, Galceran J, Canal I, Barbas A, Ferrus A | title = Frequenin--a novel calcium-binding protein that modulates synaptic efficacy in the Drosophila nervous system | journal = Neuron | volume = 11 | issue = 1 | pages = 15–28 | year = 1993 | pmid = 8101711 | doi = 10.1016/0896-6273(93)90267-U | s2cid = 30422835 }} A role in neurotransmission was later confirmed in Drosophila using frq null mutants.{{cite journal | vauthors = Dason JS, Romero-Pozuelo J, Marin L, Iyengar BG, Klose MK, Ferrus A, Atwood HL | title = Frequenin/NCS-1 and the Ca2+-channel {alpha}1-subunit co-regulate synaptic transmission and nerve-terminal growth. | journal = Journal of Cell Science | volume = 122 | issue = 22 | pages = 4109–4121 | year = 2009 | pmid = 19861494 | doi = 10.1242/jcs.055095 | s2cid = 2663472 | doi-access = }} Work in bovine chromaffin cells demonstrated that NCS-1 is also a modulator of neurotransmission in mammals.{{cite journal | vauthors = McFerran BW, Weiss JL, Burgoyne RD | title = Neuronal Ca(2+) sensor 1. Characterization of the myristoylated protein, its cellular effects in permeabilized adrenal chromaffin cells, Ca(2+)-independent membrane association, and interaction with binding proteins, suggesting a role in rapid Ca(2+) signal transduction. | journal = Journal of Biological Chemistry | volume = 274| issue = 42| pages = 30258–65|date=October 1999 | pmid = 10514519 | doi = 10.1074/jbc.274.42.30258 | doi-access = free }} The designation 'NCS-1' came from the assumption that the protein was expressed only in neuronal cell types, which is not the case.{{cite journal | vauthors = Nef S, Fiumelli H, de Castro E, Raes MB, Nef P | title = Identification of neuronal calcium sensor (NCS-1) possibly involved in the regulation of receptor phosphorylation | journal = J. Recept. Signal Transduct. Res. | volume = 15 | issue = 1–4 | pages = 365–78 | year = 1995 | pmid = 8903951 | doi = 10.3109/10799899509045227 }}

{{Reflist|2}}

{{refbegin}}

• {{cite journal | vauthors = Dason JS, Romero-Pozuelo J, Atwood HL, Ferrús A | title = Multiple roles for frequenin/NCS-1 in synaptic function and development | journal = Mol. Neurobiol. | volume = 45 | issue = 2 | pages = 388–402 |date=April 2012 | pmid = 22396213 | doi = 10.1007/s12035-012-8250-4 | hdl = 10261/60667 | s2cid = 12709387 | hdl-access = free }}
• {{cite journal | vauthors = Weiss JL, Hui H, Burgoyne RD | title = Neuronal calcium sensor-1 regulation of calcium channels, secretion, and neuronal outgrowth | journal = Cell. Mol. Neurobiol. | volume = 30 | issue = 8 | pages = 1283–92 |date=November 2010 | pmid = 21104311 | doi = 10.1007/s10571-010-9588-7 | s2cid = 2270302 | pmc = 11498851 }}

{{refend}}

• [https://web.archive.org/web/20110927134008/http://www.signaling-gateway.org/molecule/query?afcsid=A000957&type=abstract Signaling_gateway]
• [http://www.liv.ac.uk/physiology/ncs/index.html NCS proteins]

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Category:Proteins

Category:Biology of bipolar disorder