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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. NCS-1 is a member of the neuronal calcium sensor family, a class of EF hand containing calcium-myristoyl-switch proteins.
Function
NCS-1 regulates synaptic transmission, helps control the dynamics of nerve terminal growth, is critical for some forms of learning and memory in C. elegans and mammals, 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.
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 Ca-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 Ca entry through a functional interaction with the α1 voltage-gated Ca-channel subunit.
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. 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 and decreases in inflammatory bowel disease. NCS-1 has also been linked with Autism. 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.
History
NCS-1 was originally discovered in Drosophila as a gain-of-function mutation associated with frequency-dependent increases in neurotransmission. A role in neurotransmission was later confirmed in Drosophila using frq null mutants. Work in bovine chromaffin cells demonstrated that NCS-1 is also a modulator of neurotransmission in mammals. The designation 'NCS-1' came from the assumption that the protein was expressed only in neuronal cell types, which is not the case.
^ 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. PMID19861494. S2CID2663472.
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. S2CID11989516.
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.
