Neuronal calcium sensor-1

NCS1
Identifiers
Aliases	NCS1, FLUP, FREQ, neuronal calcium sensor 1
External IDs	OMIM: 603315; MGI: 109166; GeneCards: NCS1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4GUK, 1G8I, 2LCP, 5AER, 5AFP, 5AEQ
Gene location (Human) Chr. Chromosome 9 (human) Band 9q34.11 Start 130,172,404 bp End 130,237,303 bp
Gene location (Mouse) Chr. Chromosome 2 (mouse) Band 2|2 B Start 31,135,835 bp End 31,186,001 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right frontal lobe anterior cingulate cortex nucleus accumbens amygdala dorsolateral prefrontal cortex postcentral gyrus Brodmann area 9 prefrontal cortex caudate nucleus hippocampus proper Top expressed in dentate gyrus of hippocampal formation granule cell superior frontal gyrus nucleus accumbens medial geniculate nucleus subiculum medial dorsal nucleus dorsomedial hypothalamic nucleus olfactory tubercle primary visual cortex cerebellar cortex More reference expression data BioGPS n/a
Gene ontology Molecular function calcium ion binding voltage-gated calcium channel activity metal ion binding protein binding magnesium ion binding protein kinase binding voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels Cellular component cytoplasm cytosol postsynaptic membrane Golgi apparatus membrane postsynaptic density intracellular membrane-bounded organelle plasma membrane synapse axon cell junction dendrite perinuclear region of cytoplasm dense core granule cytoplasmic vesicle calyx of Held postsynapse glutamatergic synapse presynaptic cytosol postsynaptic cytosol Biological process regulation of neuron projection development calcium ion transmembrane transport positive regulation of exocytosis phosphatidylinositol-mediated signaling regulation of synaptic vesicle exocytosis regulation of presynaptic cytosolic calcium ion concentration Sources:Amigo / QuickGO
Orthologs Databases NCBI: entry; OMA: entry Species Human Mouse Entrez 23413 14299 Ensembl ENSG00000107130 ENSMUSG00000062661 UniProt P62166 Q8BNY6 RefSeq (mRNA) NM_014286 NM_001128826 NM_019681 RefSeq (protein) NP_001122298 NP_055101 NP_062655 Location (UCSC) Chr 9: 130.17 – 130.24 Mb Chr 2: 31.14 – 31.19 Mb PubMed search
Wikidata
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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. 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.

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)
   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
   12. Ric8a
3. Frq modulates Ca²⁺ entry through a functional interaction with the α₁ voltage-gated Ca²⁺-channel subunit.

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.

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. A mutant of NCS-1, R102Q, has also been found in one patient 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. Interactions of lithium ions (Li+) with NCS-1 has also been linked as a possible treatment for protection against psychotic disorders.

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.

References

Further reading

External links

• Signaling_gateway
• NCS proteins