Freezing RyR1 in its own membrane shows muscle calcium channels priming each other open

RyR1 is the largest known ion channel, and the pores that stud the sarcoplasmic reticulum membrane are what release the calcium that makes a muscle fibre contract ^[2][1]. Comparing the six states showed how one of them opens: the bulky outer part rotates within the plane of the membrane, which the team likens to turning the ring of a camera lens, while the pore widens to roughly twice its original width ^[14]. Treat that pore as circular and the open cross-section grows about fourfold, since area goes with the square of the width ^[15].

The reason to do this the hard way is in the sample preparation. "Because RyR1 is a membrane protein, you have to pull it out with detergents to purify it. But that environment can be disruptive to such a sensitive protein," Mikirtumov said ^[7]. He said the lab wanted to "capture the structure of the channel in its native membrane and find out whether its opening mechanism looks different there" ^[8].

It does. The team reports that as one channel rotates open it strains the interface with its neighbour, making it easier for the neighbour to rotate and open too ^[9]. "It's like the cogs in a clock," said Kudryashev, the senior author. "Once one cog turns, it primes its neighbors to turn, too." ^[10]

The pair evidence is statistical. Neighbouring channels were more likely to be synchronized, and two interacting closed channels were more stable than two closed channels in isolation, which the group takes as channels holding each other shut ^[16][17]. The phys.org account of the study does not say how many pairs were counted, or what resolution the reconstructions reached, and without that count the stability comparison cannot be judged ^[22].

Several disease mutations sit at the same contact. Mutations in RYR1 cause malignant hyperthermia, a life-threatening reaction to some anesthetics, and congenital myopathies that weaken muscles, and many of them alter the channel exactly where it touches its neighbour ^[18]. "A lot of these mutations don't seem to affect how a single channel opens, but rather how channels cooperate with their neighbors," Mikirtumov said ^[19].

So the structures, imaged at a cryo-electron microscopy facility run jointly by Charité, the Max Delbrück Center and the FMP ^[11], support a prediction that other experiments will have to measure: that disruption at the interface makes the channels leaky, releasing calcium when they should retain it ^[20]. Kudryashev said the group is already testing the idea. "We need to prevent the channels from opening spontaneously," he said ^[21].