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. 2012 Jul 6;10(1):17.
doi: 10.1186/1478-811X-10-17.

Role of the inositol 1,4,5-trisphosphate receptor/Ca2+-release channel in autophagy

Jan B Parys  1 , Jean-Paul Decuypere, Geert Bultynck
Affiliations

Role of the inositol 1,4,5-trisphosphate receptor/Ca2+-release channel in autophagy

Jan B Parys et al. Cell Commun Signal. .

Abstract

Autophagy is an important cell-biological process responsible for the disposal of long-lived proteins, protein aggregates, defective organelles and intracellular pathogens. It is activated in response to cellular stress and plays a role in development, cell differentiation, and ageing. Moreover, it has been shown to be involved in different pathologies, including cancer and neurodegenerative diseases. It is a long standing issue whether and how the Ca2+ ion is involved in its regulation. The role of the inositol 1,4,5-trisphosphate receptor, the main intracellular Ca2+-release channel, in apoptosis is well recognized, but its role in autophagy only recently emerged and is therefore much less well understood. Positive as well as negative effects on autophagy have been reported for both the inositol 1,4,5-trisphosphate receptor and Ca2+. This review will critically present the evidence for a role of the inositol 1,4,5-trisphosphate receptor/Ca2+-release channel in autophagy and will demonstrate that depending on the cellular conditions it can either suppress or promote autophagy. Suppression occurs through Ca2+ signals directed to the mitochondria, fueling ATP production and decreasing AMP-activated kinase activity. In contrast, Ca2+-induced autophagy can be mediated by several pathways including calmodulin-dependent kinase kinase β, calmodulin-dependent kinase I, protein kinase C θ, and/or extracellular signal-regulated kinase.

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Figures

Figure 1
Figure 1
Relation between IP3R and autophagy. IP3-induced Ca2+ release towards the mitochondria promotes ATP production, inhibition of AMPK and thus stimulation of mTOR activity. mTOR can stimulate the IP3Rs by direct phosphorylation. Inhibition of mTOR leads to the formation of the ULK1-Atg13-FIP200 complex and autophagy. In addition, the IP3R might act as scaffold for Bcl-2 and Beclin 1, thereby promoting the inhibition of Beclin 1 by Bcl-2. Beclin 1 promotes the formation of the PtdIns3K Complex III. Both complexes are necessary for the formation of the phagophore and subsequent autophagy. Ca2+ (and calmodulin) can activate multiple systems in the cell including CaMKKβ, ERK, CaMKI, PKCθ, DAPK, which phosphorylates Beclin 1, thereby mediating its dissociation from Bcl-2, and putatively also Vps34, a component of the PtdIns3K Complex III. The blue box indicates the mitochondrial (Mit.) compartment. Arrows indicate the flow of the signals; a green arrow indicates stimulation; a red arrow indicates inhibition; a double arrow indicates an interaction; a broken arrow indicates a mechanism that remains to be further defined. For more detailed explanation, see text.
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