Reducing Ca2+ leak through mutant RYR1 prevents pathological heat production in skeletal muscle.

Background Pathogenic variants in RYR1 cause a spectrum of rare congenital myopathies associated with intracellular calcium dysregulation. Glutathione redox imbalance has been reported in several Ryr1...

Effective muscle contraction relies on synchronized opening of RyR1 calcium channels. Here, authors present high-resolution structures of RyR1 in native membranes, revealing how ligand-induced activat...

Abstract. RYR1-related congenital myopathies are rare disorders that severely impair muscle function and the quality of life of patients and their families

Reducing Ca2+ leak through mutant RYR1 prevents pathological heat production in skeletal muscle.

We isolated junctional SR microsomes from rabbit skeletal muscle and examined RyR1 arrays by cryo-ET (Fig. 1a), following the previous reports20,21,23,24 with modifications, and performed high-resolution imaging of the SR vesicles in 3D by cryo-ET and in 2D for single-particle cryo-EM. While the linear two-row organization of the receptors in the muscle was perturbed, the local order was preserved with the corner-to-corner contacts clearly visible (Supplementary Fig. 1). The corner-to-corner contacts were formed via bridging-solenoid BSol domains, recapitulating the physiological arrangement of RyR1. Using a combination of SPA and StA, we determined multiple RyR1 structures under the following conditions: resting (Apo) states with and without the non-hydrolyzable ATP analog adenylyl-imidodiphosphate, denoted ACP; a Primed state induced by activating [free Ca2+] (ActCa); a mixture of Primed and Activated states in equilibrium by the addition of Ca2+, ACP, and caffeine (ActMix); and a Ryanodine-locked state with a fully dilated pore. The reconstructions had global resolutions between 3.5 Å and 4.9 Å (Supplementary Table 1). Focused refinement further improved local resolutions up to 3.0 Å in the most ordered regions, enabling building atomic models (Fig. 1b, Supplementary Figs. 2–10) and confident placement of side chains, bound ligands, and ordered lipids (Fig. 1c–f). Structural...

Malignant hyperthermia (MH) is a life-threatening pharmacogenetic condition triggered by volatile anesthetics, which activate pathogenic RyR1 mutants. The small molecule therapeutic dantrolene has lon...

brushing up with the limits of a molecule render

A new study uncovers the long-elusive mechanism of inhalational anesthetics by identifying the RyR1 calcium channel as a key molecular target.