TRPC1 expression and function inhibit ER stress and cell death in salivary gland cells

Abstract

Disturbances in endoplasmic reticulum (ER) Ca2+ homeostasis have been associated with many diseases including loss of salivary glands. Although significant progress has been accomplished which led to the increase in our understanding of the cellular responses to ER stress, the factors/ion channels that could inhibit ER stress are not yet identified. Here we show that TRPC1 (transient receptor potential canonical 1) is involved in regulating Ca2+ homeostasis and loss of TRPC1 decreased ER Ca2+ levels, inhibited the unfolded protein response (UPR), that induced loss of salivary gland cells. We provide further evidence that ER stress inducing agents (Tunicamycin and Brefeldin A) disrupts Ca2+ homeostasis by directly inhibiting TRPC1-mediated Ca2+ entry, which led to ER stress in salivary gland cells. Moreover, induction of ER stress lead to an increase in CHOP expression, which decreased TRPC1 expression and subsequently attenuated autophagy along with increased apoptosis. Importantly, TRPC1−/− mice showed increased ER stress, increased immune cell infiltration, loss of Ca2+ homeostasis, decreased saliva secretion, and decreased salivary gland survival. Finally, restoration of TRPC1 not only maintained Ca2+ homeostasis, but inhibited ER stress that induced cell survival. Overall these results suggest a significant role of TRPC1 Ca2+ channels in ER stress and homeostatic function/survival of salivary gland cells.

Transient Receptor Potential Ankyrin-1 and Vanilloid-3 Differentially Regulate Endoplasmic Reticulum Stress and Cytotoxicity in Human Lung Epithelial Cells After Pneumotoxic Wood Smoke Particle Exposure

“…In general, TRPV3 over-expression conferred protection against ERS induced by most of these agents, based on decreases in the level of DDIT3 induction (i.e., the pro-apoptotic branch of the ERS response). These data imply a possible selective effect of TRPV3 on PERK-dependent signaling, which may result from TRPV3 promoting calcium homeostasis, as has been suggested for TRPC1 in salivary gland cells (Sukumaran et al, 2019). Accordingly, the induction of TRPV3 in conjunction with suppressed TRPA1 expression may indicate a deliberate process by which cells attempt to restore the balance of ER and cytosolic calcium concentrations to limit ERS and other pathological processes, wherein TRPA1 and TRPV3 play central roles.…”

Calcium Signaling Regulates Autophagy and Apoptosis

“…TRPC1 plays a vital role in hypoxia and nutrient-depletion-dependent autophagy in both excitable and non-excitable cells [67]. The silencing of TRPC1 channels attenuates the increase in autophagy markers and thereby upregulates the apoptotic markers [67,68]. Drugs (tunicamycin and neurotoxins) attenuated autophagy and increased apoptosis through a decrease in TRPC1 function, leading to ER stress [68,69].…”

Investigation of the effect of hyperthyroidism on endoplasmic reticulum stress and tran- sient receptor potential canonical 1 channel in the kidney

“…on CHOP expression. Increased ER stress and infiltration in salivary gland cells of TRPC1 -/knock-out mice were observed [16].…”

“…Severe Ca 2+ disorders may trigger cell damage caused by endoplasmic reticulum (ER) stress in response to various pathological conditions [5,15]. Disorders in Ca 2+ homeostasis in ER are associated with many diseases [16]. ER is an intracellular organelle that is important for regulating Ca 2+ homeostasis and protein synthesis and folding.…”