How dantrolene binds and closes a calcium channel in malignant hyperthermia

Structures of the calcium-release channel RyR1 show how the emergency drug works with ADP or ATP to promote channel closure.

Editorial illustration — not from the study.

Malignant hyperthermia is a life-threatening reaction to some anesthetics in people with disease-causing variants in RyR1, a channel that releases calcium inside muscle cells. Dantrolene has long been used to treat the condition, but its binding site and mechanism had been unclear.

Using cryo-electron microscopy, the researchers mapped dantrolene’s binding site and compared RyR1 with the channel bound to the trigger compound 4-chloro-m-cresol. Dantrolene binds alongside ATP or ADP in a region called the RY12 domain, causing a shape change that is linked to closure of the channel’s pore.

Where dantrolene binds

The cryo-electron microscopy structures showed dantrolene bound in the RY12 domain, at a corner of the RyR1 receptor, stacked with ATP or ADP. Functional tests found that ATP or ADP was required for dantrolene to inhibit RyR1. A single mutation that disrupted a peripheral ATP-binding site eliminated this ATP- or ADP-dependent inhibition.

Without dantrolene, the same site selectively bound two ADP molecules. This suggests that the RY12 domain may help RyR1 sense the balance between ATP and ADP, although the study describes this as a possible role rather than a directly established function.

Why the binding site matters

The findings provide a structural explanation for how dantrolene acts on RyR1 during malignant hyperthermia: it binds near ATP or ADP, changes the shape of the channel and is linked to pore closure. Identifying this binding site and its dependence on ATP or ADP clarifies the action of a long-used treatment and points to a role for the channel in sensing cellular energy status.

Evidence and caveats

The study combines atomic-detail cryo-electron microscopy structures with functional analyses of RyR1 and a targeted mutation. These results directly identify the binding sites and show that ATP or ADP is required for dantrolene inhibition in the tested system. The abstract does not provide details about the number of experiments, the full range of disease-causing RyR1 variants tested or how well the findings translate to patients. The proposed role of the site in sensing the ATP-to-ADP balance remains a possibility suggested by the structures, not a demonstrated physiological function.

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