Editors' ChoiceCalcium signaling

Modulating Intraorganelle Communication

Science's STKE  06 Nov 2007:
Vol. 2007, Issue 411, pp. tw400
DOI: 10.1126/stke.4112007tw400

The endoplasmic reticulum (ER) releases calcium signals to the mitochondria through inositol 1,4,5-trisphosphate receptors (IP3Rs) located at contacts known as mitochondrion-associated ER membrane (MAM). ER calcium can also influence protein folding by ER chaperones, many of which are calcium-binding proteins up-regulated in response to ER stress (such as calcium depletion). Hayashi and Su found that, in CHO cells, the sigma-1 receptor (Sig-1R, an ER protein implicated in neuroplasticity and neuroprotection) was apposed to mitochondria. Fractionation analysis revealed that Sig-1R was enriched in the MAM fraction, as were several calcium-binding chaperones, including BiP [the immunoglobulin heavy chain-binding protein, also known as glucose-regulated protein 78 (GRP78)]. Sig-1R coimmunoprecipitated with BiP, an association that depended on calcium; ER calcium depletion led to dissociation of Sig-1R from BiP, as did several psychotropic drugs and steroids that act as Sig-1R ligands. Sig-1R acted as a chaperone in vitro, and in calcium-free medium--but not medium containing calcium--the chaperone effects of Sig-1R and BiP were additive. Calcium depletion (through IP3R activation or pharmacological manipulation) promoted the association of Sig-1R with type 3 IP3Rs (IP3R3); although the Sig-1R ligand (+)pentazocine did not itself stimulate association between Sig-1R and IP3R3, it prolonged their association in response to calcium depletion. Sig-1Rs inhibited the IP3-dependent degradation of IP3R3 and modulated calcium signaling to the mitochondria. Various ER stressors stimulated an increase in Sig-1R mRNA and protein and, eventually, its redistribution throughout the ER. Thus, the authors propose that Sig-1Rs represent a ligand- and calcium-modulated ER chaperone that acts to regulate ER-mitochondrial signaling.

T. Hayashi, T.-P. Su, Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131, 596-610 (2007). [PubMed]