STIM Proteins: The Gas and Brake of Calcium Entry in Neurons

Abstract

Stromal interaction molecules (STIM)s are Ca²⁺ sensors in internal Ca²⁺ stores of the endoplasmic reticulum. They activate the store-operated Ca²⁺ channels, which are the main source of Ca²⁺ entry in non-excitable cells. Moreover, STIM proteins interact with other Ca²⁺ channel subunits and active transporters, making STIMs an important intermediate molecule in orchestrating a wide variety of Ca²⁺ influxes into excitable cells. Nevertheless, little is known about the role of STIM proteins in brain functioning. Being involved in many signaling pathways, STIMs replenish internal Ca²⁺ stores in neurons and mediate synaptic transmission and neuronal excitability. Ca²⁺ dyshomeostasis is a signature of many pathological conditions of the brain, including neurodegenerative diseases, injuries, stroke, and epilepsy. STIMs play a role in these disturbances not only by supporting abnormal store-operated Ca²⁺ entry but also by regulating Ca²⁺ influx through other channels. Here, we review the present knowledge of STIMs in neurons and their involvement in brain pathology.

Keywords: Brain; Calcium; Calcium channels; Calcium entry; Neurons; STIM1; STIM2.

Fig. 1

The schematic structure of STIM1 and STIM2 proteins with their splice variants STIM1A, STIM1B, STIM1L, STIM2.1, and STIM2.3. The N-terminus of STIM faces the ER lumen and contains canonical and hidden EF-hands and a SAM, as well as a transmembrane domain (TM). The C-terminus of STIM faces the cytosol and may contain 3 coiled-coil domains (CC1-3), an ID, a plus-EB domain, and a poly-lysine tract (PolyK). The double arrow denotes interaction domains: the SOAR and domains interacting with lipids, homer proteins, and CaM.

Fig. 2

Physiological and experimental activation of STIM proteins. STIMs are activated by a drop of Ca²⁺ in the ER, form oligomers, and translocate to the proximity of the PM. The Ca²⁺ store depletion is a result of the activation of G_q-coupled receptor (G_qPCR) signaling pathways, activating phospholipase C (PLC), and hydrolyzing PIP₂ to IP₃ and DAG_. IP₃ activates IP₃ receptors (IP₃Rs). IP₃Rs and RyRs (ryanodine receptors) are Ca²⁺ channels of the ER and their stimulation triggers the release of Ca²⁺ from the ER. Sarco-/endoplasmic reticulum Ca²⁺ ATPases (SERCAs) store Ca²⁺ in the ER depot. In experiments, the blockade of SERCA leads to passive store depletion through ER leakage channels. The low-Ca²⁺ condition in the ER may be also reproduced upon treatment with Ca²⁺-chelators. Independently of the ER Ca²⁺ level, STIMs may be activated by temperature. In addition, optogenetic STIM variants may be utilized in the research on STIM signaling pathways. Those molecules are represented by LOV2- and arCRY2-based chimeras, which are either localized in the cytosol or tethered to the ER.

Fig. 3

STIM proteins and their targets in neurons. STIMs interact with store-operated Ca²⁺ channels, including TRPC and Orai1-formed channels, L- and T-type voltage-operated Ca²⁺ channels, AMPA-receptors (GluA1 and GluA2 subunits), NMDA-receptors (NMDA2A and NMDA2B subunits), and pannexin-1 (Panx1) channels. In addition, STIMs may stimulate the lysosomal TRPML1 channel. Na⁺/Ca²⁺-exchanger 1 (NCX1) may also work together with TRPC channels, driving Ca²⁺ into the cytosol.