Neuronal STIMulation at rest

Abstract

Almost a decade has passed since first STIM, and later Orai, proteins were identified as the molecular constituents of store-operated calcium entry (SOCE). Their roles in immune function have been intensely investigated, but the roles of STIM and Orai in neuronal cells have been much less clear. Lalonde et al. show that when neurons are hyperpolarized or "at rest," constitutive endoplasmic reticulum (ER) Ca(2+) release leads to SOCE-mediated activation of neuronal transcription factors. Precisely why ER Ca(2+) release is constitutive in neurons remains an important question. Irrespective of the answer, this observation provides an intriguing new perspective on why a relatively low-abundance, small-conductance channel such as Orai1 would be important in neurons, which contain a relative abundance of voltage-operated Ca(2+) channels.

Fig. 1. Control of ER Ca²⁺ content in neurons

The proteins and pathways pertinent to Ca²⁺ homeostasis in neurons are shown, with relative localized Ca²⁺ concentration indicated by blue shading. The plasma membrane Ca²⁺-ATPase (PMCA) is responsible for extrusion of Ca²⁺ from the cell. The neuron can be considered in four parts. In the first part, the neuron has hyperpolarized, blocking VGCC activity and causing ER Ca²⁺ depletion. In the second part, ER Ca²⁺ depletion activates STIM and engages Orai, enabling SERCA activity and refilling the ER Ca²⁺ content. In the third part, the resting neuron with some amount of ER Ca²⁺ depletion becomes depolarized, but the activated STIM inhibits VGCC activation. In the fourth part, the ER Ca²⁺ content of the activated neuron has recovered, leading to VGCC activity, disengagement of STIM, and normal ER Ca²⁺ content.