Functional role of TRP channels in modulating ER stress and Autophagy

Abstract

Intracellular calcium (Ca2+) levels play a vital role in regulating cellular fate. The coordination and interrelation among the cellular organelles, mainly the intracellular Ca2+ stores in endoplasmic reticulum (ER), are crucial in maintaining cytosolic Ca2+ levels and in general cellular homeostasis. Moreover, maintaining Ca2+ homeostasis is essential for regulating diverse and sometimes opposing processes such as cell survival and cell death in disease conditions such as, neurodegeneration, cancer and aging. Ca2+ is able to regulate opposing functions by either regulating the cellular “self-eating” phenomenon of autophagy to promote cell survival or by regulating the programmed cell death process of apoptosis. Autophagy is also important for cell survival especially after induction of ER stress and association between ER stress and autophagy may have relevance to numerous diseases. Moreover, a multitude of evidence is emerging that the functional regulation of TRP channels, their unique localization, and their interaction with other Ca2+-sensing elements define these diverse regulatory pathways. It is this unique function which allows individual TRP channels to contribute differently in the regulation of cell fate and, in turn, determines the precise effect of modulating Ca2+ signaling via the particular channel. Thus, in this review we have focused on the aspects of TRP channel localization and function (Ca2+ signaling) that affects the ER stress and autophagic process.

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

“…Similarly, the expression of downstream targets of pPERK, like BiP, phosphor—e1F2 alpha and CHOP expression were also increased in cells treated with either SKF, Tu, or BFA (Figure A). One of the puzzling results in our studies was why expression of TRPC1 was decreased in ER stress conditions and also ER stress‐mediated cell death has been shown to be dependent on CHOP expression ; thus, we silenced CHOP and evaluated its effect on TRPC1 expression and Ca 2+ entry. Inhibition of CHOP expression using siRNA (siCHOP), significantly decreased Tu‐induced increase in CHOP expression (Figure B).…”

Crosstalk between calcium and reactive oxygen species signaling in cancer

“…Recently, attention has been placed on the mucolipin TRPML channel family members in the regulation of autophagy, given their localization to lysosomal membranes and influence on Ca 2+ signaling in these organelles [3, 164]. Autophagy is regulated by a number of cellular stressors, including nutrient deprivation, and the unfolded protein response/ER stress, which are closely associated with oxidative stress [44].…”

“…It should be pointed out that there are conflicting reports on the role of IP 3 R on both promoting and suppressing autophagy, which is likely dependent on nutrient availability (i.e. culture conditions), cell type and feedback mechanisms of Ca 2+ signaling that control autophagy regulators such as Beclin I [164]. Many tumor cells are thought to survive without oxidative phosphorylation, relying primarily on aerobic glycolysis.…”

ROS and Ca 2+ —Partners in sickness and in health

“…Sukumaran et al [42] highlight the role of TRPC channels in modulating ER stress and autophagy. They discuss recent findings showing that the ER Ca 2+ store is crucial in maintaining cellular homeostasis and serves as a checkpoint for opposing processes leading to cell survival or death.…”