Keeping pain away by distancing the plasma membrane from the endoplasmic reticulum

Abstract

Cytoplasmic Ca2+ signals regulate many biological processes, including muscle contraction, neurotransmitter release and hormone secretion. The two major sources of increased cytoplasmic Ca2+ are the extracellular space and the endoplasmic reticulum (ER). In many cell types, there is an intricate crosstalk between the ER, or equivalent intracellular membrane compartments, and the plasma membrane in regulating Ca2+ homeostasis. One classical example is the skeletal muscle, where the action potential initiated in the plasma membrane travels down the T-tubule and activates voltage gated Ca2+ channels (dihydropyridine receptors), which in turn activate the Ca2+ release channel ryanodine receptors via protein-protein interaction in the membrane of the sarcoplasmic reticulum (SR) (Fig. 1A). This signalling mechanism requires the maintenance of the physical proximity between the SR and the T-tubule. This is achieved by various adaptor proteins, including junctophilin-1 (Landstrom et al. 2014), which bridges the gap between the two membranes and keeps them together (Fig. 1A). Another more recently discovered signalling paradigm where the close proximity of the plasma membrane and the ER is critical is the store operatedCa2+ entry through Orai1 channels. Plasma membrane receptors that couple to heterotrimeric Gq proteins, activate phospholipase C enzymes leading to the formation of the second messenger inositol 1,4,5 trisphosphate (IP3). IP3 binds to its receptor in the ER, which leads to the release of Ca2+ to the cytoplasm, and to decreased Ca2+ content in the ER. The decrease in ER Ca2+ is sensed by STIM1 proteins, which aggregate and move closer to the plasma membrane, and activate Orai1 channels by protein-protein interaction (Woo et al. 2018) (Fig. 1B). This signalling mechanism was also shown to require various adaptor proteins that stabilize the plasmamembrane ER junctions (Woo et al. 2018). One of these proteins is junctophilin-4, which was shown to regulate Ca2+ dynamics in T-lymphocytes (Woo et al. 2016) (Fig. 1B). Store operated Ca2+ entry was originally described in non-excitable cells such as epithelial cells and T-lymphocytes. However, its role is emerging in a variety of excitable cells, including peripheral sensory neurons of the dorsal root ganglia (DRG), where it has been shown to regulate nociception, the detection of painful stimuli (Munoz & Hu, 2016). In this issue of The Journal of Physiology, Hogea et al. (2021) address the role of junctophilins in nociceptive DRG neurons. The authors stained rat DRG neurons with antibodies against all four junctophilin isoforms (JPH1-4), and identified junctophilin-4 as the dominant isoform, with some expression of JPH1 and JPH3, but not JPH2. Importantly, JPH4 showed a high degree of co-expression with STIM1