全周 (9AM - 6PM)

我们和你在一起

Extra info thumb
NEURONAL CALCIUM SENSOR 1; NCS1

NEURONAL CALCIUM SENSOR 1; NCS1

Alternative titles; symbolsFREQUENIN, DROSOPHILA, HOMOLOG OF; FREQHGNC Approved Gene Symbol: NCS1Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): ...

Alternative titles; symbols

  • FREQUENIN, DROSOPHILA, HOMOLOG OF; FREQ

HGNC Approved Gene Symbol: NCS1

Cytogenetic location: 9q34.11 Genomic coordinates (GRCh38): 9:130,172,403-130,237,302 (from NCBI)

▼ Description
Frequenin, a member of a large family of myristoyl-switch calcium-binding proteins, functions as a calcium-ion sensor to modulate synaptic activity and secretion (Bourne et al., 2001).

▼ Cloning and Expression
De Castro et al. (1995) cloned the rat and C. elegans orthologs of NCS1. Amino acid sequence analysis of rat NCS1 detected 3 potential EF-hand calcium-binding domains.

Using information from previously cloned mammalian homologs of Drosophila Frq, Bourne et al. (2001) cloned human FREQ from first-strand cDNA. FREQ encodes a deduced 190-amino acid protein that shares 100% amino acid identity with the mouse and rat homologs and over 99% identity with the Xenopus homolog. FREQ and its yeast homolog are also highly homologous, with 75% of amino acids either identical or corresponding to conservative replacements. The human protein contains 4 EF-hand motifs that represent potential Ca(2+)-binding domains, and a consensus sequence for myristoylation in the N terminus.

▼ Biochemical Features
Crystal Structure

Bourne et al. (2001) determined the crystal structure of unmyristoylated, calcium-bound human frequenin to 1.9-angstrom resolution. Its overall fold is similar to those of other family members such as recoverin, with 2 pairs of calcium-binding hands and 3 bound calcium ions. Frequenin does, however, have significant structural differences, including a novel large conformation shift of the C terminus that creates a wide hydrophobic crevice at the surface of the protein.

▼ Gene Function
De Castro et al. (1995) showed that several calcium sensors, including NCS1, recoverin (179618), VILIP (600817), and S-modulin, can inhibit rhodopsin (180380) phosphorylation in a calcium-dependent manner.

McFerran et al. (1998) found that NCS1, the mammalian homolog of Drosophila frequenin, is expressed not only in bovine neurons, but also in neuroendocrine cells. Colocalization and fractionation assays showed that NCS1 may be associated with secretory granules. McFerran et al. (1998) concluded that NCS1 may be involved in the regulation of neurosecretion.

Nakamura et al. (2001) provided direct evidence that frequenin strongly and specifically modulates Kv4 channels (the molecular components of subthreshold-activating A-type K+ currents). The effect was specific for Kv4.2 currents (605410); frequenin had negligible effects on Kv4.1 current inactivation time course. Coimmunoprecipitation experiments demonstrated that a physical interaction occurs between frequenin and Kv4.2 protein in brain membranes.

Bourne et al. (2001) determined that frequenin colocalizes with ARF1 GTPase (103180) in COS-7 cells and occurs in similar cellular compartments as the phosphatidylinositol-4-OH kinase PI4K-beta (602758), the mammalian homolog of the yeast kinase PIK1.

In a Xenopus model of the neuromuscular junction, Wang et al. (2001) demonstrated that frequenin acted downstream of glial-derived neurotrophic factor (GDNF; 600837) to enhance presynaptic calcium efflux via N-type calcium channels, resulting in increased synaptic transmission. P/Q-type presynaptic calcium currents undergo activity-dependent facilitation during repetitive activation at the calyx of the Held synapse. Tsujimoto et al. (2002) demonstrated that direct loading of NCS1 into the nerve terminal mimicked activity-dependent P/Q-type presynaptic calcium current facilitation by accelerating the activation time of the current in a calcium-dependent manner. A presynaptically loaded carboxyl-terminal peptide of NCS1 abolished the presynaptic calcium current facilitation. Tsujimoto et al. (2002) concluded that residual calcium activates endogenous NCS1, thereby facilitating P/Q-type presynaptic calcium currents. Because both the calcium channels and NCS1 are widely expressed in mammalian nerve terminals, NCS1 may contribute to the activity-dependent synaptic facilitation at many synapses.

In cultured rat hippocampal cells, Sippy et al. (2003) showed that increases in NCS1 can switch paired-pulse depression to facilitation without altering basal synaptic transmission or initial neurotransmitter release probability. Facilitation persisted during high-frequency trains of stimulation, indicating that NCS1 can recruit dormant vesicles. Sippy et al. (2003) suggested that NCS1 acts as a calcium sensor for short-term synaptic plasticity by facilitating neurotransmitter output.

By screening a human fetal brain library using a yeast 2-hybrid system with the intracellular domain of IL1RAPL (300206) as bait, Bahi et al. (2003) determined that IL1RAPL interacts with NCS1 through its specific C-terminal domain. Transient transfection and immunostaining detected both proteins in the cytosol and demonstrated significant overlap in the staining at the periphery of the transfected cells, suggesting a colocalization at the plasma membrane.

Gromada et al. (2005) found that Ncs1 increased exocytosis in rodent pancreatic beta cells by promoting priming of secretory granules for release and increasing the number of granules residing in the readily releasable pool. The effect of Ncs1 on exocytosis was mediated through increased Pi4k-beta activity and generation of phosphoinositides, specifically phosphatidylinositol 4-phosphate (PtdIns(4)P) and PtdIns(4,5)P2. In turn, PtdIns(4,5)P2 controlled exocytosis through Ca(2+)-dependent activator protein for secretion (CADPS; 604667). Gromada et al. (2005) concluded that NCS1 and its downstream target, PI4K-beta, are critical for glucose-induced insulin secretion due to their capacity to regulate the release competence of secretory granules.

▼ Mapping
By sequence analysis, Bourne et al. (2001) mapped the FREQ gene to chromosome 9q34.

Tags: 9q34.11