Biology:Neuronal calcium sensor-1

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Short description: Neuronal calcium sensory protein


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Neuronal calcium sensor-1 (NCS-1) also known as frequenin homolog (Drosophila) (freq) is a protein that is encoded by the FREQ gene in humans.[1] NCS-1 is a member of the neuronal calcium sensor family,[2] a class of EF hand containing calcium-myristoyl-switch proteins.[3]

Function

NCS-1 regulates synaptic transmission,[4] helps control the dynamics of nerve terminal growth,[5][6][4] is critical for some forms of learning and memory in C. elegans[7] and mammals,[8] regulates corticohippocampal plasticity; and enhancing levels of NCS-1 in the mouse dentate gyrus increases spontaneous exploration of safe environments,[8] potentially linking NCS-1 to curiosity.[9]

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).
    1. Calcineurin (protein phosphatase 2B)
    2. GRK2 (G-protein-coupled receptor kinase 2)
    3. D2 dopamine receptor
    4. IL1RAPL1 (interleukin-1 receptor accessory protein-like 1 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)[10]
    7. 3',5'-cyclic nucleotide phosphodiesterases
    8. ARF1 (ADP Ribosylation factor 1)
    9. A type (Kv4.3; Shal-related subfamily, member 3) voltage-gated potassium channels
    10. Nitric oxide synthase
    11. TRPC5 channel[11]
    12. Ric8a[12]
  3. Frq modulates Ca2+ entry through a functional interaction with the α1 voltage-gated Ca2+-channel subunit.[4]

Structure

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.[13] 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.

Clinical significance

The expression of NCS-1 increases in bipolar disorder and some forms of schizophrenia[14] and decreases in inflammatory bowel disease.[15] NCS-1 has also been linked with Autism.[16] 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.[17]

History

NCS-1 was originally discovered in Drosophila as a gain-of-function mutation associated with frequency-dependent increases in neurotransmission.[18] A role in neurotransmission was later confirmed in Drosophila using frq null mutants.[4] Work in bovine chromaffin cells demonstrated that NCS-1 is also a modulator of neurotransmission in mammals.[19] The designation 'NCS-1' came from the assumption that the protein was expressed only in neuronal cell types, which is not the case.[20]

References

  1. ↑ "Immunocytochemical localization and crystal structure of human frequenin (neuronal calcium sensor 1)". J. Biol. Chem. 276 (15): 11949–55. April 2001. doi:10.1074/jbc.M009373200. PMID 11092894. 
  2. ↑ Burgoyne RD (2007). "Neuronal calcium sensor proteins: generating diversity in neuronal Ca2+ signalling". Nat. Rev. Neurosci. 8 (3): 182–193. doi:10.1038/nrn2093. PMID 17311005. 
  3. ↑ "Neuronal Ca2+-sensor proteins: multitalented regulators of neuronal function". Trends Neurosci. 27 (4): 203–9. 2004. doi:10.1016/j.tins.2004.01.010. PMID 15046879. 
  4. ↑ 4.0 4.1 4.2 4.3 "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. 2009. doi:10.1242/jcs.055095. PMID 19861494. 
  5. ↑ "Chronic and acute alterations in the functional levels of Frequenins 1 and 2 reveal their roles in synaptic transmission and axon terminal morphology.". European Journal of Neuroscience 26 (9): 2428–2443. 2007. doi:10.1111/j.1460-9568.2007.05877.x. PMID 17970740. 
  6. ↑ "Neuronal calcium sensor-1 modulation of optimal calcium level for neurite outgrowth.". Development 134 (24): 4479–4489. 2007. doi:10.1242/dev.008979. PMID 18039973. 
  7. ↑ "Ca2+ signaling via the neuronal calcium sensor-1 regulates associative learning and memory in C. elegans". Neuron 30 (1): 241–8. 2001. doi:10.1016/S0896-6273(01)00276-8. PMID 11343658. 
  8. ↑ 8.0 8.1 "NCS-1 in the dentate gyrus promotes exploration, synaptic plasticity, and rapid acquisition of spatial memory". Neuron 63 (5): 643–56. 2009. doi:10.1016/j.neuron.2009.08.014. PMID 19755107. 
  9. ↑ McDermott, Melissa (September 14, 2009). "Researchers discover the first-ever link between intelligence and curiosity". PHYS ORG. http://phys.org/news172174436.html. 
  10. ↑ "Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium". J. Clin. Invest. 116 (6): 1668–74. 2006. doi:10.1172/JCI22466. PMID 16691292. 
  11. ↑ "Calcium-sensing mechanism in TRPC5 channels contributing to retardation of neurite outgrowth". J. Physiol. 572 (Pt 1): 165–72. April 2006. doi:10.1113/jphysiol.2005.102889. PMID 16469785. 
  12. ↑ "The guanine-exchange factor Ric8a binds to the Ca2+ sensor NCS-1 to regulate synapse number and neurotransmitter release.". Journal of Cell Science 127 (19): 4246–4259. 2014. doi:10.1242/jcs.152603. PMID 25074811. 
  13. ↑ "Functional Status of Neuronal Calcium Sensor-1 Is Modulated by Zinc Binding". Frontiers in Molecular Neuroscience 11: 459. 2018. doi:10.3389/fnmol.2018.00459. PMID 30618610. PMC 6302015. https://hal-amu.archives-ouvertes.fr/hal-01955226/file/fnmol-11-00459.pdf. 
  14. ↑ "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. 2003. doi:10.1073/pnas.232693499. PMID 12496348. Bibcode: 2003PNAS..100..313K. 
  15. ↑ "Intestinal inflammation modulates expression of the synaptic vesicle protein neuronal calcium sensor-1". Am. J. Physiol. Gastrointest. Liver Physiol. 282 (6): G1097–104. 2002. doi:10.1152/ajpgi.00320.2001. PMID 12016136. 
  16. ↑ "Structural and functional deficits in a neuronal calcium sensor-1 mutant identified in a case of autistic spectrum disorder". PLOS ONE 5 (5): e10534. 2010. doi:10.1371/journal.pone.0010534. PMID 20479890. Bibcode: 2010PLoSO...510534H. 
  17. ↑ McDermott, Melissa. "Researchers discover the first-ever link between intelligence and curiosity" (in en). http://www.physorg.com/news172174436.html. 
  18. ↑ "Frequenin--a novel calcium-binding protein that modulates synaptic efficacy in the Drosophila nervous system". Neuron 11 (1): 15–28. 1993. doi:10.1016/0896-6273(93)90267-U. PMID 8101711. 
  19. ↑ "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 of Biological Chemistry 274 (42): 30258–65. October 1999. doi:10.1074/jbc.274.42.30258. PMID 10514519. 
  20. ↑ "Identification of neuronal calcium sensor (NCS-1) possibly involved in the regulation of receptor phosphorylation". J. Recept. Signal Transduct. Res. 15 (1–4): 365–78. 1995. doi:10.3109/10799899509045227. PMID 8903951. 

Further reading

External links



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