Neuronal calcium sensor-1

Neuronal calcium sensor 1
PDB rendering based on 1g8i.
Available structures PDB 1g8i
Identifiers
Symbols	NCS1; DKFZp761L1223; FLUP; FREQ
External IDs	OMIM: 603315 MGI: 109166 HomoloGene: 5719 GeneCards: NCS1 Gene
Gene Ontology Molecular function • calcium ion binding • protein binding Cellular component • cytoplasm • Golgi apparatus • cytosol • plasma membrane • postsynaptic density • cell junction • axon • dendrite • dense core granule • cytoplasmic vesicle • Golgi cisterna membrane • intracellular membrane-bounded organelle • synapse • postsynaptic membrane • perinuclear region of cytoplasm Biological process • regulation of neuron projection development • positive regulation of exocytosis • phosphatidylinositol-mediated signaling • negative regulation of calcium ion transport via voltage-gated calcium channel activity Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	23413	14299
Ensembl	ENSG00000107130	ENSMUSG00000062661
UniProt	P62166	Q8BNY6
RefSeq (mRNA)	NM_001128826.1	NM_019681.3
RefSeq (protein)	NP_001122298.1	NP_062655.1
Location (UCSC)	Chr 9: 132.93 – 133 Mb	Chr 2: 31.1 – 31.15 Mb
PubMed search	[1]	[2]

Neuronal calcium sensor-1 (NCS-1) also known as frequenin homolog (Drosophila) (freq) is a protein that in humans is encoded by the FREQ gene.^[1] This protein regulates G protein-coupled receptor phosphorylation in a calcium-dependent manner and can substitute for calmodulin.^[2]

NCS-1 is a member of neuronal calcium sensor family which^[3], are EF hand containing calcium-myristoyl-switch proteins ^[4] . This calcium binding protein was originally discovered in Drosophila melanogaster and named Frequenin (Frq).^[5] Drosophila null frq mutants have impaired neurotransmitter release and enhanced nerve terminal growth.^[6] NCS-1 has a known role in learning and memory in C. elegans^[7] and mammals^[8]. NCS-1 is a calcium sensor, not a calcium buffer (chelator); thus it is a high-affinity, low-capacity, calcium-binding protein.

Structure

NCS1 has four EF-hand motifs. Each motif has a 12-amino-acid loop.

Function

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).
   1. Calcineurin (protein phosphatase 2B)
   2. GRK2 (G-protein-coupled receptor kinase 2)
   3. D₂ dopamine receptor
   4. IL1RAPL (interleukin-1 receptor accessory protein-like protein)
   5. PI4KIIIβ (type III phosphatidylinositol 4-kinase β)
   6. IP3 receptor (this activity is inhibited by lithium - a drug used for the treatment of bipolar disorder)^[9]
   7. 3',5'-cyclic nucleotide phosphodiesterases
   8. ARF1 (ADP Ribosylation factor 1)
   9. A type (K_v4.3; Shal-related subfamily, member 3) voltage-gated potassium channels
   10. Nitric oxide synthase
   11. TRPC5 channel^[10]
3. Frq modulates Ca²⁺ entry through a functional interaction with the α₁ voltage-gated Ca²⁺-channel subunit.^[6]

History

NCS-1 was originally discovered in Drosophila as a mutation associated with calcium stimulated increases in neurotransmission. Later work in bovine chromaffin cells confirmed NCS-1 as a modulator of neurotransmission.^[11] The designation 'NCS-1' came from the assumption that the protein was expressed only in neuronal cell types, which is not the case.^[12]

Clinical significance

The expression of NCS-1 increases in bipolar disorder and some forms of schizophrenia^[13] and decreases in inflammatory bowel disease.^[14] NCS-1 has also been linked with Autism: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866544/?tool=pubmed.

References

1. ^ Bourne Y, Dannenberg J, Pollmann V, Marchot P, Pongs O (April 2001). "Immunocytochemical localization and crystal structure of human frequenin (neuronal calcium sensor 1)". J. Biol. Chem. 276 (15): 11949–55. doi:10.1074/jbc.M009373200. PMID 11092894. 
2. ^ De Castro E, Nef S, Fiumelli H, Lenz SE, Kawamura S, Nef P (November 1995). "Regulation of rhodopsin phosphorylation by a family of neuronal calcium sensors". Biochem. Biophys. Res. Commun. 216 (1): 133–40. doi:10.1006/bbrc.1995.2601. PMID 7488079. 
3. ^ Burgoyne RD (2007). "Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+ signalling". Nat. Rev. Neurosci. 8 (3): 182–193. doi:10.1038/nrn2093. PMC 1887812. PMID 17311005. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1887812. 
4. ^ Burgoyne RD, O'Callaghan DW, Hasdemir B, Haynes LP, Tepikin AV (2004). "Neuronal Ca2+-sensor proteins: multitalented regulators of neuronal function". Trends Neurosci. 27 (4): 203–9. doi:10.1016/j.tins.2004.01.010. PMID 15046879. 
5. ^ 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. (1993). "Frequenin--a novel calcium-binding protein that modulates synaptic efficacy in the Drosophila nervous system". Neuron 11 (1): 15–28. doi:10.1016/0896-6273(93)90267-U. PMID 8101711. 
6. ^ ^{a b} Dason JS, Romero-Pozuelo J, Marin L, Iyengar BG, Klose MK, Ferrus A, Atwood HL. (2009). "Frequenin/NCS-1 and the Ca2+-channel {alpha}1-subunit co-regulate synaptic transmission and nerve-terminal growth.". Journal of Cell Science 122 (22): 4109–4121. doi:10.1242/jcs.055095. PMID 19861494. 
7. ^ Gomez M, De Castro E, Guarin E, Sasakura H, Kuhara A, Mori I, Bartfai T, Bargmann CI, Nef P. (2001). "Ca2+ signaling via the neuronal calcium sensor-1 regulates associative learning and memory in C. elegans". Neuron 30 (1): 241–8. doi:10.1016/S0896-6273(01)00276-8. PMID 11343658. 
8. ^ Saab BJ, Georgiou J, Nath A, Lee FJ, Wang M, Michalon A, Liu F, Mansuy IM, Roder JC. (2009). "NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory". Neuron 63 (5): 643–56. doi:10.1016/j.neuron.2009.08.014. PMID 19755107. 
9. ^ Schlecker C, Boehmerle W, Jeromin A, DeGray B, Varshney A, Sharma Y, Szigeti-Buck K, Ehrlich BE (2006). "Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium". J. Clin. Invest. 116 (6): 1668–74. doi:10.1172/JCI22466. PMC 1459068. PMID 16691292. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1459068. 
10. ^ Hui H, McHugh D, Hannan M, Zeng F, Xu SZ, Khan SU, Levenson R, Beech DJ, Weiss JL (April 2006). "Calcium-sensing mechanism in TRPC5 channels contributing to retardation of neurite outgrowth". J. Physiol. (Lond.) 572 (Pt 1): 165–72. doi:10.1113/jphysiol.2005.102889. PMC 1779652. PMID 16469785. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1779652. 
11. ^ Weiss JL, Hui H, Burgoyne RD (November 2010). "Neuronal Calcium Sensor-1 Regulation of Calcium Channels, Secretion, and Neuronal Outgrowth". Cell Mol Neurobiol 30 (8): 1283–1292. doi:10.1007/s10571-010-9588-7. PMID 21104311. 
12. ^ S. Nef, H. Fiumelli, E. de Castro, M. B. Raes & P. Nef (January-March 1995). "Identification of neuronal calcium sensor (NCS-1) possibly involved in the regulation of receptor phosphorylation". Journal of receptor and signal transduction research 15 (1-4): 365–378. doi:10.3109/10799899509045227. PMID 8903951. 
13. ^ Koh PO, Undie AS, Kabbani N, Levenson R, Goldman-Rakic PS, Lidow MS. (2003). "Up-regulation of neuronal calcium sensor-1 (NCS-1) in the prefrontal cortex of schizophrenic and bipolar patients". Proc Natl Acad Sci U S A. 100 (1): 313–7. doi:10.1073/pnas.232693499. PMC 140961. PMID 12496348. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=140961. 
14. ^ Lourenssen S, Jeromin A, Roder J, Blennerhassett MG (2002). "Intestinal inflammation modulates expression of the synaptic vesicle protein neuronal calcium sensor-1". Am. J. Physiol. Gastrointest. Liver Physiol. 282 (6): G1097–104. doi:10.1152/ajpgi.00320.2001. PMID 12016136. 

External links

• Signaling_gateway
• NCS proteins