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


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.


Higo, T., et al.