NCS1 Human

NCS-1 is a high-affinity, low-capacity calcium-binding protein that is ubiquitously expressed, with the highest abundance in neuronal tissues . It is N-terminally myristoylated, which allows it to bind intracellular membranes . The protein primarily transduces calcium signals through interactions with its target proteins, including dopamine receptor D2 (D2R), voltage-gated calcium channels (Cavs), and inositol 1,4,5-trisphosphate receptors (InsP3Rs) . These interactions modulate various downstream effects such as neurotransmission, synaptic plasticity, neurite outgrowth, and neuronal survival .

NCS-1 has been implicated in several neurological and psychiatric conditions, including autism spectrum disorder (ASD), fragile X syndrome, Parkinson’s disease, Alzheimer’s disease, bipolar disorder, and schizophrenia . Knockout studies in model organisms like Caenorhabditis elegans and mice have shown that the absence of NCS-1 results in impaired memory and learning . Conversely, overexpression of NCS-1 in the dentate gyrus of mice enhances synaptic plasticity and memory .

NCS-1 regulates synaptic transmission and helps control the dynamics of nerve terminal growth . It is critical for some forms of learning and memory in both C. elegans and mammals . The protein also regulates corticohippocampal plasticity, and enhancing levels of NCS-1 in the mouse dentate gyrus increases spontaneous exploration of safe environments . This potentially links NCS-1 to curiosity .

In addition to calcium ions, NCS-1 can bind mobile, or signaling, intracellular zinc, which is a characteristic feature of cells under oxidative stress . Zinc coordination under these conditions stimulates NCS-1 oxidation to form a disulfide dimer (dNCS-1) with altered functional properties . This combined effect of mobile zinc and increased redox potential can induce aberrant NCS-1 activity, promoting either the survival of neuronal cells or their apoptosis, potentially leading to neurodegenerative processes .