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Neuronal calcium sensor-1 (NCS-1) also known as frequenin homolog (Drosophila) (freq) is a protein that is encoded by the FREQgene in humans.[5] NCS-1 is a member of the neuronal calcium sensor family,[6] a class of EF hand containing calcium-myristoyl-switch proteins.[7]
Function
NCS-1 regulates synaptic transmission,[8] helps control the dynamics of nerve terminal growth,[9][10][8] is critical for some forms of learning and memory in C. elegans[11] and mammals,[12] regulates corticohippocampal plasticity; and enhancing levels of NCS-1 in the mouse dentate gyrus increases spontaneous exploration of safe environments,[12] potentially linking NCS-1 to curiosity.[13]
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.
It is the Ca2+-sensing subunit of the yeast phosphatidylinositol (PtdIns)-4-OH kinase, PIK1
It binds to many proteins, some in calcium dependent and some in calcium independent ways, and switches many of the targets "on" (some off).
Frq modulates Ca2+ entry through a functional interaction with the α1 voltage-gated Ca2+-channel subunit.[8]
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 [17]. 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.
NCS-1 was originally discovered in Drosophila as a gain-of-function mutation associated with frequency-dependent increases in neurotransmission.[21] A role in neurotransmission was later confirmed in Drosophila using frq null mutants.[8] Work in bovine chromaffin cells demonstrated that NCS-1 is also a modulator of neurotransmission in mammals.[22] The designation 'NCS-1' came from the assumption that the protein was expressed only in neuronal cell types, which is not the case.[23]
^Romero-Pozuelo J, Dason JS, Atwood HL, Ferrus A (2007). "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. doi:10.1111/j.1460-9568.2007.05877.x. hdl:10261/72998. PMID17970740.
^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. PMID11343658.
^ abSaab 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. PMID19755107.
^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. PMID8101711.
^Nef S, Fiumelli H, de Castro E, Raes MB, Nef P (1995). "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. doi:10.3109/10799899509045227. PMID8903951.
Further reading
Dason JS, Romero-Pozuelo J, Atwood HL, Ferrús A (April 2012). "Multiple roles for frequenin/NCS-1 in synaptic function and development". Mol. Neurobiol. 45 (2): 388–402. doi:10.1007/s12035-012-8250-4. hdl:10261/60667. PMID22396213.