Neuronal calcium sensor-1 regulation of calcium channels, secretion, and neuronal outgrowth

Abstract

Calcium (Ca(2+)) is an important intracellular messenger underlying cell physiology. Ca(2+) channels are the main entry route for Ca(2+) into excitable cells, and regulate processes such as neurotransmitter release and neuronal outgrowth. Neuronal Calcium Sensor-1 (NCS-1) is a member of the Calmodulin superfamily of EF-hand Ca(2+) sensing proteins residing in the subfamily of NCS proteins. NCS-1 was originally discovered in Drosophila as an overexpression mutant (Frequenin), having an increased frequency of Ca(2+)-evoked neurotransmission. NCS-1 is N-terminally myristoylated, can bind intracellular membranes, and has a Ca(2+) affinity of 0.3 μM. Over 10 years ago it was discovered that NCS-1 overexpression enhances Ca(2+)-evoked secretion in bovine adrenal chromaffin cells. The mechanism was unclear, but there was no apparent direct effect on the exocytotic machinery. It was revealed, again in chromaffin cells, that NCS-1 regulates voltage-gated Ca(2+) channels (Cavs) in G-Protein Coupled Receptor (GPCR) signaling pathways. This work in chromaffin cells highlighted NCS-1 as an important modulator of neurotransmission. NCS-1 has since been shown to regulate and/or directly interact with many proteins including Cavs (P/Q, N, and L), TRPC1/5 channels, GPCRs, IP3R, and PI4 kinase type IIIβ. NCS-1 also affects neuronal outgrowth having roles in learning and memory affecting both short- and long-term synaptic plasticity. It is not known if NCS-1 affects neurotransmission and synaptic plasticity via its effect on PIP2 levels, and/or via a direct interaction with Ca(2+) channels or their signaling complexes. This review gives a historical account of NCS-1 function, examining contributions from chromaffin cells, PC12 cells and other models, to describe how NCS-1's regulation of Ca(2+) channels allows it to exert its physiological effects.

Fig. 1

Model of NCS-1 dual regulation of Cavs and secretion where NCS-1 acts as a mediator of neurotransmission. The lines depict NCS-1’s effect on secretion and Cav channels. An arrow with a + represents an effect to increase activity while one with a − depicts a decrease in activity. NCS-1 can enhance secretion via its activation of PI4 kinaseIIIβ and the subsequent increase in PIP2 levels leading to an increase in IP3 mediated internal Ca²⁺ store release. This increase in Ca²⁺ levels will increase vesicle motility to drive vesicles to fuse with the plasma membrane to release their contents. In addition, plasma membrane pools of PIP2 itself promote vesicle fusion and motility. PIP2 can also stabilize Cav channels (N-type) function and this can be enhanced via NCS-1 due to its activation of PI4 kinaseIIIβ and the subsequent rise in PIP2 levels. NCS-1 can also inhibit Cavs (P/Q-type) via its signaling in a purinergic GPCR inhibition pathway. The exact mechanism of how NCS-1 inhibits P/Q-type Cavs is unknown but data indicates that a PTX insensitive G-protein and a Src-like kinase are involved (Weiss and Burgoyne 2001)