Neurological and Motor Disorders: Neuronal Store-Operated Ca2+ Signaling: An Overview and Its Function

Abstract

Calcium (Ca²⁺) is a ubiquitous second messenger that performs significant physiological task such as neurosecretion, exocytosis, neuronal growth/differentiation, and the development and/or maintenance of neural circuits. An important regulatory aspect of neuronal Ca²⁺ homeostasis is store-operated Ca²⁺ entry (SOCE) which, in recent years, has gained much attention for influencing a variety of nerve cell responses. Essentially, activation of SOCE ensues following the activation of the plasma membrane (PM) store-operated Ca²⁺ channels (SOCC) triggered by the depletion of endoplasmic reticulum (ER) Ca²⁺ stores. In addition to the TRPC (transient receptor potential canonical) and the Orai family of ion channels, STIM (stromal interacting molecule) proteins have been baptized as key molecular regulators of SOCE. Functional significance of the TRPC channels in neurons has been elaborately studied; however, information on Orai and STIM components of SOCE, although seems imminent, is currently limited. Importantly, perturbations in SOCE have been implicated in a spectrum of neuropathological conditions. Hence, understanding the precise involvement of SOCC in neurodegeneration would presumably unveil avenues for plausible therapeutic interventions. We thus review the role of SOCE-regulated neuronal Ca²⁺ signaling in selecting neurodegenerative conditions.

Keywords: Calcium; Neurodegenerative diseases; Oxidative and ER stress; TRPC.

Fig. 27.1

Store-operated Ca²⁺ entry and neuronal function. This illustration depicts the current understanding of SOCE regulated by STIM1-mediated activation of PM-SOCC (TRPC/Orai channels). Agonist-induced activation of PM receptors (GPCR/RTK) results in the generation of the diffusible cellular messenger IP₃ following the PLC-mediated hydrolysis of PIP₂. IP₃ binds to its receptor (IP₃R) in the ER depleting the ER Ca²⁺ stores. This leads to STIM1 oligomerization and recruitment of the STIM1-clusters to ER-PM juxtaposed sites where STIM1 physically gates the TRPC and Orai1 channels to bring about Ca²⁺ entry. This raises the [Ca²⁺]_cyt which not only aids in the SERCA pump-mediated ER store refilling but also promotes the regulation of several cellular functions. Additionally, diacylglycerol (DAG), the membrane-associated lipid messenger also has the ability to activate select TRPC channels independent of the ER store and presumably STIM1 as well.

Fig. 27.2

Consequences of abnormal Ca²⁺ signaling. This illustration depicts the current understanding of the consequences of abnormal Ca²⁺ signaling. Altered Ca²⁺ signaling leads to issues such as oxidative stress, ROS production, Ca²⁺ overload, unfolded protein response and ER stress, mitochondrial and lysosomal dysfunction and inhibition of autophagy. This leads to loss of neuronal function and induction of neuronal diseases.