Calcium channel signalling at neuronal endoplasmic reticulum-plasma membrane junctions

Abstract

Neurons are highly specialised cells that need to relay information over long distances and integrate signals from thousands of synaptic inputs. The complexity of neuronal function is evident in the morphology of their plasma membrane (PM), by far the most intricate of all cell types. Yet, within the neuron lies an organelle whose architecture adds another level to this morphological sophistication - the endoplasmic reticulum (ER). Neuronal ER is abundant in the cell body and extends to distant axonal terminals and postsynaptic dendritic spines. It also adopts specialised structures like the spine apparatus in the postsynapse and the cisternal organelle in the axon initial segment. At membrane contact sites (MCSs) between the ER and the PM, the two membranes come in close proximity to create hubs of lipid exchange and Ca2+ signalling called ER-PM junctions. The development of electron and light microscopy techniques extended our knowledge on the physiological relevance of ER-PM MCSs. Equally important was the identification of ER and PM partners that interact in these junctions, most notably the STIM-ORAI and VAP-Kv2.1 pairs. The physiological functions of ER-PM junctions in neurons are being increasingly explored, but their molecular composition and the role in the dynamics of Ca2+ signalling are less clear. This review aims to outline the current state of research on the topic of neuronal ER-PM contacts. Specifically, we will summarise the involvement of different classes of Ca2+ channels in these junctions, discuss their role in neuronal development and neuropathology and propose directions for further research.

Keywords: ER-PM junctions; ORAI; STIM; endoplasmic reticulum; membrane contact sites; store-operated calcium entry.

Figure 1.. Overview of proteins that regulate Ca²⁺ signals in neuronal ER-PM junctions.

The ER extends throughout the whole neuron, including the soma, dendrites and axons, and adopts specialised forms like the cisternal organelle and the spine apparatus. Notice that although ER-PM junctions are present in all neuronal compartments, the ER does not come in direct contact with the active zone (AZ) of neurotransmitter secretion or with the postsynaptic density (PSD) [1]. Letters denote the most important or newly identified ER-PM partners that are described in the main text. (A) Somatic plasma membrane K_v2.1 channels cluster with VAP proteins in the ER and recruit Ca_v1.2 and RyRs to ER-PM junctions to regulate excitation-transcription coupling [71,75,76]; (B and C) it has been suggested that VGCC-RyR and ORAI-IP₃R pairs create two functionally independent ER Ca²⁺ pools [61]; (D) ORAI was implied to impact neuronal excitability [53–57]; (E) axonal ER in developing neurons was shown to adopt a ladder-like morphology, with STIM1 molecules colocalising with ORAI1 in structures termed ‘ER rungs’ [120]; (F) presynaptic STIMs were reported to play a role in neurotransmitter release via activation of ORAIs (by STIM2) [14] and by control of axonal ER Ca²⁺ stores (by STIM1) [15]; (G) VAP-K_v2.1 clusters are implicated in activity-dependent uptake of Ca²⁺ to axonal ER, loss of K_v2.1 impaired action-potential evoked Ca²⁺ influx into the presynapse and the release of neurotransmitter [16]; (H) STIM1 was shown to provide NMDAR-dependent feedback-inhibition of Ca_v1.2 channels to limit excessive Ca²⁺ influx during glutamatergic neurotransmission [44]; (I) neuronal insults impact the morphology of ER-PM junctions: treatment with high doses of extracellular NMDA, which mimics glutamate spillover, significantly decreased the extent of ER-PM junctions [83], while nerve injury increased it [165]; (J) there is evidence for a direct interaction of STIM proteins with NMDA and AMPA receptors, impacting their activity and trafficking [39–43]; (K) TRPCs are a diverse family of proteins that can act as store-operated channels [45,46]; (L) pannexin has recently been identified as another store-operated channel; its activation is coupled to NMDARs and controlled by STIM1 [89]. Red dots represent glutamate. K_v2.1, voltage-gated potassium channel 2.1; Ca_v1.2, 2.1, 2.2, voltage-gated Ca²⁺ channels 1.2, 2.1, 2.2; VAP, VAMP-associated protein; RyR, ryanodine receptor; JPH, junctophilin; SERCA, sarco-/endopolasmic reticulum Ca²⁺ ATPase; STIM, stromal interaction molecule; IP₃R, inositol triphosphate receptor; NMDAR, NMDA receptor; AMPAR, AMPA receptor; TRPC, transient receptor potential channel; PANX, pannexin; AZ, active zone; PSD, postsynaptic density. Figure created with BioRender®.