Neuronal calcium sensor-1


Neuronal calcium sensor-1 also known as frequenin homolog 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 ; 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 -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".
  3. # Calcineurin
  4. # Beta [adrenergic receptor kinase|GRK2]
  5. # D2 dopamine receptor
  6. # IL1RAPL1
  7. # PI4KIIIβ
  8. # IP3 receptor
  9. # 3',5'-cyclic nucleotide phosphodiesterases
  10. # ARF1
  11. # A type voltage-gated potassium channels
  12. # Nitric oxide synthase
  13. # TRPC5 channel
  14. # Ric8a
  15. 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. Elevation of free Zn²⁺ 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. 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 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.