NCS-1 is a regulator of calcium signaling in health and disease

Abstract

Neuronal Calcium Sensor-1 (NCS-1) is a highly conserved calcium binding protein which contributes to the maintenance of intracellular calcium homeostasis and regulation of calcium-dependent signaling pathways. It is involved in a variety of physiological cell functions, including exocytosis, regulation of calcium permeable channels, neuroplasticity and response to neuronal damage. Over the past 30 years, continuing investigation of cellular functions of NCS-1 and associated disease states have highlighted its function in the pathophysiology of several disorders and as a therapeutic target. Among the diseases that were found to be associated with NCS-1 are neurological disorders such as bipolar disease and non-neurological conditions such as breast cancer. Furthermore, alteration of NCS-1 expression is associated with substance abuse disorders and severe side effects of chemotherapeutic agents. The objective of this article is to summarize the current body of evidence describing NCS-1 and its interactions on a molecular and cellular scale, as well as describing macroscopic implications in physiology and medicine. Particular attention is paid to the role of NCS-1 in development and prevention of chemotherapy induced peripheral neuropathy (CIPN).

Keywords: CIPN; Calcium binding proteins; Calcium signaling; Cancer chemotherapy; Paclitaxel; Peripheral neuropathy.

Fig. 1. Interaction of NCS-1 and InsP3R

(A) Upon binding of InsP₃, the InsP₃R releases calcium from the ER. (B) NCS-1 alone is not sufficient to activate InsP₃R. (C) Binding of NCS-1 enhances InsP₃ mediated InsP₃R channel activity by increasing the open probability and mean open time. (D) Lithium offsets NCS-1 mediated enhancing effects on InsP₃R. (E) Paclitaxel binds the hydrophobic cleft of NCS-1 in calcium-bound state. Thereby it facilitates binding of NCS-1 to InsP₃R, thus inducing calcium oscillations. (F) Lithium (as well as ibudilast) inhibit paclitaxel mediated, NCS-1 dependent increases in InsP₃R channel activity, preventing calcium oscillations. Note that many NCS-1 molecules are membrane bound.

Fig. 2. A model of desired and unwanted drug effects

After application, a drug can operate through several pathways that entail different molecular players and lead to distinct positive therapeutic effects (green) and undesired side effects (red). Because Pathway C (blue) mediates only side effects, it is an ideal target for pharmacological intervention. In contrast, intervention of ’Pathway B’ comes with the risk of compromising desired effects because this pathway leads to both wanted and undesired effects.

Fig. 3. Possible pathophysiological pathway of CIPN

Paclitaxel facilitates binding of NCS-1 to InsP₃R, thereby inducing Ca²⁺ oscillations from the ER. The increased cytosolic Ca²⁺ is further enhanced through activation of Ca²⁺ dependent TRPV4 channels. Ca²⁺ activates the Ca²⁺ dependent protease calpain, which cleaves and a number of other proteins. This creates a negative feedback loop and impairs signaling through the InsP₃R. This leads to an attenuation of Ca²⁺ oscillations. Impaired signaling and further degradation of proteins lead to axonal damage and cell death. Lithium and ibudilast both interact with NCS-1 and prevent enhanced InsP₃R activity and NCS-1 protein degradation. TRPV4 inhibitor HC-067047 reduces mechanical allodynia after paclitaxel treatment. BAPTA and other Ca2+ reducing agents have been shown to inhibit the pathway. Overexpression of calpastatin, an endogenous calpain inhibitor, as well as overexpression of NCS-1 mutations (I35H or I35A) were able to protect WT NCS-1 in human neuroblastoma cells.