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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | NCS1 , FLUP, FREQ, neuronal calcium sensor 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 603315; MGI: 109166; HomoloGene: 5719; GeneCards: NCS1; OMA:NCS1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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 FREQ gene 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]
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.
Additionally, NCS-1 is redox-sensitive: under oxidizing conditions it forms a covalent disulfide-linked dimer via Cys38 (dNCS-1). Elevation of free Zn²⁺ (as during oxidative stress) specifically promotes this dimerization, whereas increasing intracellular Ca²⁺ does not. The dimer binds Ca²⁺ in only one EF-hand per monomer, displays reduced α-helicity and thermal stability with increased surface hydrophobicity, and shows ~20-fold higher affinity for GRK1 accompanied by stronger inhibition of the kinase. dNCS-1 can also coordinate Zn²⁺ and exhibits asymmetrical, more flexible subunits. In cells, dNCS-1 is reduced by the thioredoxin system; otherwise it accumulates in perinuclear puncta and aggregates targeted by the proteasome. Notably, NCS-1 silencing decreases susceptibility to oxidative-stress-induced apoptosis in Y79 cells, implicating NCS-1 in redox-regulated survival pathways. [17]
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. [18] 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 [19] and decreases in inflammatory bowel disease. [20] A mutant of NCS-1, R102Q, has also been found in one patient with Autism. [21] 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. [22] Interactions of lithium ions (Li+) with NCS-1 has also been linked as a possible treatment for protection against psychotic disorders. [23]
NCS-1 was originally discovered in Drosophila as a gain-of-function mutation associated with frequency-dependent increases in neurotransmission. [24] 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. [25] The designation 'NCS-1' came from the assumption that the protein was expressed only in neuronal cell types, which is not the case. [26]
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