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 [Tu] and Brefeldin A [BFA]) disrupt 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 C/EBP homologous protein (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 also 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.
Highlights
Calcium is a ubiquitous second messenger that modulates most of the cellular functions including gene expression and cellular homeostasis,[1,2] neurotransmitter release and neuronal function,[3,4] and modulation of metabolism and cell survival.[5]
Our results clearly show that blocking transient receptor potential canonical channel‐1 (TRPC1) activity or loss of TRPC1 expression inhibited Ca2+ homeostasis that lead to endoplasmic reticulum (ER) stress
The properties of the Ca2+ entry channel in Human salivary gland (HSG) cells were similar to those previously observed with TRPC1 channels 26 which showed a reverse potential around 0 mV and were nonselective (Figure 2D). Both Tu and Brefeldin A (BFA) treatment decreased the Ca2+ currents, it did not alter the channel properties. These results suggest that TRPC1 channel is the major Ca2+ entry channel in these cells, which is affected upon the induction of ER stress
Summary
Calcium is a ubiquitous second messenger that modulates most of the cellular functions including gene expression and cellular homeostasis,[1,2] neurotransmitter release and neuronal function,[3,4] and modulation of metabolism and cell survival.[5]. This Ca2+ influx replenishes the ER Ca2+ stores, thereby maintaining its ability to release Ca2+ upon subsequent stimuli This is critical since Ca2+ concentrations within the ER must be maintained at sufficient levels for the organelle to carry out many of its fundamental functions.[8,9,10] Previous studies from our laboratory and others have shown that transient receptor potential canonical channel‐1 (TRPC1) is involved in regulating Ca2+ homeostasis in salivary gland cells.[16] Interestingly, in human salivary epithelial cell lines, TRPC1 has shown to be the major Ca2+ influx channel and knockdown of TRPC1 inhibited salivary gland function; its role in ER stress is not yet established. Our data provided the mechanism where ER stress‐induced expression of CHOP modulates TRPC1 expression, which further inhibits Ca2+ homeostasis and inhibits autophagy that increases apoptosis in human salivary cells
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