Apoptosis and Autophagy: Decoding Calcium Signals that Mediate Life or Death

Abstract

Calcium is a versatile and dynamic 2nd messenger that is essential for the survival of all higher organisms. In cells that undergo activation or excitation, calcium is released from the endoplasmic/sarcoplasmic reticulum to activate calcium-dependent kinases and phosphatases, thereby regulating numerous cellular processes; for example, apoptosis and autophagy. In the case of apoptosis, endogenous ligands or pharmacological agents induce prolonged cytosolic calcium elevation, which in turn leads to cell death. In contrast, there is now evidence that calcium regulates autophagy by several mechanisms, and these may be important for maintaining cell survival. Here we summarize what is known about how calcium regulates these life and death decisions. We pay particular attention to pathways that have been described in lymphocytes and cardiomyocytes, as these systems provide optimal models for understanding calcium signaling in the context of normal cell physiology.

Phosphorylated K-Ras limits cell survival by blocking Bcl-xL sensitization of inositol trisphosphate receptors

“…Calcium signaling is an important mechanism that regulates autophagy (33). We recently showed that the constitutive flux of calcium from the ER to mitochondria through IP3Rs is essential to suppress autophagy under conditions of abundant nutrients (14).…”

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

“…The Ca 2 þ -level in HCT116 cells is enhanced in response to 5-FU treatment Ca 2 þ is a ubiquitous second messenger involved in many cellular processes, including cell death. 20,21 Ca 2 þ fluxes from the extracellular space are determined by the activity of voltageoperated, receptor-operated and store-operated membrane channels that normally are under tight control. Elevated Ca 2 þ level in the cytoplasmic compartment can also occur as a result of release from the endoplasmic reticulum, which is the major organelle involved in Ca 2 þ homeostasis.…”

Fragmented Inositol 1,4,5-Trisphosphate Receptors Retain Tetrameric Architecture and Form Functional Ca2+ Release Channels

“…Apoptosis is an evolutionary conserved process vital for normal development and is also implicated in the etiology of many human diseases. Notably, many current cellular models of apoptosis posit that prolonged and sustained elevations of the intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i )can be an important event for the initiation and/or progression of the apoptotic cascade (14,15). Moreover, numerous reports have suggested that altered IP 3 R activity is involved in apoptosis in a variety of cell types (reviewed in Ref.…”

“…A prominent example is the role of intracellular Ca 2ϩ elevations in contributing to programmed cell death, or apoptosis (12)(13)(14). Apoptosis is an evolutionary conserved process vital for normal development and is also implicated in the etiology of many human diseases.…”