Regulatory Mechanisms of Endoplasmic Reticulum Resident IP3 Receptors

Abstract

Dysregulated calcium signaling and accumulation of aberrant proteins causing endoplasmic reticulum stress are the early sign of intra-axonal pathological events in many neurodegenerative diseases, and apoptotic signaling is initiated when the stress goes beyond the maximum threshold level of endoplasmic reticulum. The fate of the cell to undergo apoptosis is controlled by Ca2(+) signaling and dynamics at the level of the endoplasmic reticulum. Endoplasmic reticulum resident inositol 1,4,5-trisphosphate receptors (IP3R) play a pivotal role in cell death signaling by mediating Ca2(+) flux from the endoplasmic reticulum into the cytosol and mitochondria. Hence, many prosurvival and prodeath signaling pathways and proteins affect Ca2(+) signaling by directly targeting IP3R channels, which can happen in an IP3R-isoform-dependent manner. Here, in this review, we summarize the regulatory mechanisms of inositol triphosphate receptors in calcium regulation and initiation of apoptosis during unfolded protein response.

Ca2+ transport and signalling in enamel cells

“…Three predominant IP 3 R isoforms have been described (IP 3 R1, IP 3 R2 and IP 3 R3) in vertebrates with 60–80% homology in their amino acid sequences (Shah et al . ). IP 3 Rs are encoded by several genes with a number of isoforms formed through splicing (Foskett et al .…”

Inositol 1,4,5-Trisphosphate Receptor Type 3 Regulates Neuronal Growth Cone Sensitivity to Guidance Signals

“…Although we demonstrated that growth cone sensitivity can be controlled by intracellular signaling at the IP 3 R level, it remains unclear how this regulation occurs under physiological conditions. One possible mechanism is phosphorylation of IP 3 R subunits (reviewed in Mikoshiba, 2007;Shah et al, 2015;Vanderheyden et al, 2009). For example, cAMP-dependent protein kinase A (PKA) phosphorylates IP 3 R3 at three known sites: serines 916, 934, and 1832, in contrast to only one for each of IP 3 R1 or IP 3 R2.…”

Calcium Dynamics Mediated by the Endoplasmic/Sarcoplasmic Reticulum and Related Diseases

“…ATP binds to the purinergic receptor P2YR, a GPCR, triggering production of IP 3 that binds to the IP 3 R to release Ca 2+ from the ER [64,65]. IP 3 R1 was also found to be activated by thiol modification with less than 10 µM of thimerosal, having more than this concentration actually caused an inhibitory effect [66]. Additionally, IP 3 R can be phosphorylated through protein kinase A (PKA), protein kinase B (PKB), cycline-dependent kinase 1 (CDK1), and MAP kinases [66].…”