Endoplasmic reticulum Ca²⁺ homeostasis and neuronal death

Abstract

The endoplasmic reticulum (ER) is a universal signalling organelle, which regulates a wide range of neuronal functional responses. Calcium release from the ER underlies various forms of intracellular Ca 2+ signalling by either amplifying Ca 2+ entry through voltage-gated Ca 2+ channels by Ca 2+ -induced Ca 2+ release (CICR) or by producing local or global cytosolic calcium fluctuations following stimulation of metabotropic receptors through inositol-1,4,5-trisphosphate-induced Ca 2+ release (IICR). The ER Ca 2+ store emerges as a single interconnected pool, thus allowing for a long-range Ca 2+ signalling via intra-ER tunnels. The fluctuations of intra-ER free Ca 2+ concentration regulate the activity of numerous ER resident proteins responsible for post-translational protein folding and modification. Disruption of ER Ca 2+ homeostasis results in the developing of ER stress response, which in turn controls neuronal survival. Altered ER Ca 2+ handling may be involved in pathogenesis of various neurodegenerative diseases including brain ischemia and Alzheimer dementia.

Activation of Protein Kinase C in Sensory Neurons Accelerates Ca2+Uptake into the Endoplasmic Reticulum

“…An increase in SERCA-mediated Ca 2ϩ uptake could influence neurotoxic processes. Accelerating [Ca 2ϩ ] i clearance might protect from Ca 2ϩ overload (Nicholls and Budd, 2000;Orrenius et al, 2003;Verkhratsky and Toescu, 2003). Alternatively, full ER Ca 2ϩ stores are a prerequisite for some apoptotic pathways, so accelerated refilling of the ER could exacerbate toxic processes (Szabadkai and Rizzuto, 2004 In summary, we found that activation of PKC accelerated SERCA-mediated Ca 2ϩ uptake into the ER.…”

Elevated Testosterone Induces Apoptosis in Neuronal Cells

“…In general, this occurs when the Ca 2ϩ signal differs from the pattern expected for a specific stimulus. For example, modifying the amplitude or duration of the Ca 2ϩ signals can lead to cell death (28). Here we show that testosterone can induce concentration-dependent patterns of Ca 2ϩ signals.…”

“…It is this pathway that has been implicated in other pathophysiological conditions. For example, overstimulation of the apoptotic program in neurons has been associated with several neurological illnesses, such as Alzheimer disease (27,28) and Huntington disease (29 -31). Our results suggest that the responses to elevated testosterone can be compared with these pathophysiological conditions.…”

Overview of cell death signaling pathways

“…ER-stress-mediated apoptosis might have an important role in the pathogenesis of these neurodegenerative diseases. 210 Neuronal death by ER stress also occurs after injury from ischemia or toxic drugs, such as methamphetamine or nitric oxide. 339 Adult neuronal death also occurs by necrosis, an unregulated cell death that is the direct result of external insults such as physical injury, energy depletion, toxic insults, hypoxia and ischemia.…”