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Lumen cues calcium release

ERp44 (red) binds to the lumenal side of IP3R1 (green) to inhibit calcium release. MIKOSHIBA/ELSEVIER

Calcium release from lumenal stores is sensitive to the redox state of the ER lumen, as shown by Takayasu Higo, Katsuhiko Mikoshiba (University of Tokyo, Japan), and colleagues. The group has identified the first ER lumenal protein that controls IP₃-regulated calcium channels (IP₃Rs).The opening of IP₃Rs is tightly controlled by cytosolic conditions. Most scientists assume that conditions in the ER also regulate channel opening, but the evidence was minimal. To find any relevant regulators in the ER, the authors used a lumenal domain of IP₃R1 to fish out binding proteins. They discovered ERp44, whose association with IP₃R1 blocked IP₃-induced calcium release.

But the binding of ERp44 and IP₃R1, and subsequent channel blockage, depended on several conditions. First, the association occurred at low calcium levels, as would be seen after ER calcium stores are depleted. Second, it required that the lumenal domain of the channel be in its reduced state, with free thiol groups.

That ERp44 is sensitive to the redox state is not surprising—ERp44 is a member of the thioredoxin family and can either donate or accept electrons from other proteins. But this is the first demonstratoin that oxidative stress, as occurs during inflammation, may deplete calcium stores.

"If the channel is oxidized," says Mikoshiba, "it's open, and letting out calcium," resulting in calcium depletion. "Then ERp44 comes along...changes [IP₃R1] to the reduced state [by donating electrons], binds, and blocks the channel." Strong reducing conditions, which are unfavorable for protein folding, would also keep the channel closed, thus maintaining the high calcium levels that ER chaperones need.

Calcium oscillations resulting from calcium release from the store are important in fertility and neuronal activity. The new findings suggest that these processes may be disrupted by oxidative stress.

Reference:

Higo, T., et al. 2005. Cell. 120:85–98.[CrossRef][Medline]

Nicole LeBrasseur

lebrasn{at}rockefeller.edu

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This Article Full Text (PDF, 345K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by LeBrasseur, N. Search for Related Content PubMed Articles by LeBrasseur, N. Social Bookmarking                            What's this?