Neuronal calcium sensor-1 (NCS-1) also known as frequenin homolog (Drosophila) (freq) is a
protein that is encoded by the FREQgene 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]
Function
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.
It is the Ca2+-sensing subunit of the yeast phosphatidylinositol (PtdIns)-4-OH kinase,
PIK1
It binds to many proteins, some in calcium dependent and some in calcium independent ways, and switches many of the targets "on" (some off).
Frq modulates Ca2+ entry through a functional interaction with the α1 voltage-gated Ca2+-channel subunit.[8]
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.[17] 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[18] and decreases in
inflammatory bowel disease.[19] NCS-1 has also been linked with Autism.[20] 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.[21]
History
NCS-1 was originally discovered in Drosophila as a gain-of-function mutation associated with frequency-dependent increases in
neurotransmission.[22] 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.[23] The designation 'NCS-1' came from the assumption that the protein was expressed only in neuronal cell types, which is not the case.[24]
^
abcdDason JS, Romero-Pozuelo J, Marin L, Iyengar BG, Klose MK, Ferrus A, Atwood HL (2009). "Frequenin/NCS-1 and the Ca2+-channel {alpha}1-subunit co-regulate synaptic transmission and nerve-terminal growth". Journal of Cell Science. 122 (22): 4109–4121.
doi:
10.1242/jcs.055095.
PMID19861494.
S2CID2663472.
^Romero-Pozuelo J, Dason JS, Atwood HL, Ferrus A (2007). "Chronic and acute alterations in the functional levels of Frequenins 1 and 2 reveal their roles in synaptic transmission and axon terminal morphology". European Journal of Neuroscience. 26 (9): 2428–2443.
doi:
10.1111/j.1460-9568.2007.05877.x.
hdl:10261/72998.
PMID17970740.
S2CID11989516.
^Nef S, Fiumelli H, de Castro E, Raes MB, Nef P (1995). "Identification of neuronal calcium sensor (NCS-1) possibly involved in the regulation of receptor phosphorylation". J. Recept. Signal Transduct. Res. 15 (1–4): 365–78.
doi:
10.3109/10799899509045227.
PMID8903951.
Neuronal calcium sensor-1 (NCS-1) also known as frequenin homolog (Drosophila) (freq) is a
protein that is encoded by the FREQgene 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]
Function
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.
It is the Ca2+-sensing subunit of the yeast phosphatidylinositol (PtdIns)-4-OH kinase,
PIK1
It binds to many proteins, some in calcium dependent and some in calcium independent ways, and switches many of the targets "on" (some off).
Frq modulates Ca2+ entry through a functional interaction with the α1 voltage-gated Ca2+-channel subunit.[8]
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.[17] 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[18] and decreases in
inflammatory bowel disease.[19] NCS-1 has also been linked with Autism.[20] 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.[21]
History
NCS-1 was originally discovered in Drosophila as a gain-of-function mutation associated with frequency-dependent increases in
neurotransmission.[22] 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.[23] The designation 'NCS-1' came from the assumption that the protein was expressed only in neuronal cell types, which is not the case.[24]
^
abcdDason JS, Romero-Pozuelo J, Marin L, Iyengar BG, Klose MK, Ferrus A, Atwood HL (2009). "Frequenin/NCS-1 and the Ca2+-channel {alpha}1-subunit co-regulate synaptic transmission and nerve-terminal growth". Journal of Cell Science. 122 (22): 4109–4121.
doi:
10.1242/jcs.055095.
PMID19861494.
S2CID2663472.
^Romero-Pozuelo J, Dason JS, Atwood HL, Ferrus A (2007). "Chronic and acute alterations in the functional levels of Frequenins 1 and 2 reveal their roles in synaptic transmission and axon terminal morphology". European Journal of Neuroscience. 26 (9): 2428–2443.
doi:
10.1111/j.1460-9568.2007.05877.x.
hdl:10261/72998.
PMID17970740.
S2CID11989516.
^Nef S, Fiumelli H, de Castro E, Raes MB, Nef P (1995). "Identification of neuronal calcium sensor (NCS-1) possibly involved in the regulation of receptor phosphorylation". J. Recept. Signal Transduct. Res. 15 (1–4): 365–78.
doi:
10.3109/10799899509045227.
PMID8903951.