Neuronal calcium sensor-1

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.

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.

External links

• Signaling_gateway
• NCS proteins