The role of subunit cooperativity on ryanodine receptor 2 calcium signaling

Greene, D’Artagnan; Luchko, Tyler; Shiferaw, Yohannes

doi:10.1016/j.bpj.2022.11.008

Cited by 8 publications

(1 citation statement)

References 48 publications

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“…Given the existence of multiple propofol binding sites distributed among different domains in this very large protein, we hypothesize that an allosteric mechanism at least partly underlies its effects, although this is conjectural. One possibility is disruption of subunit cooperativity, shown in a kinetic model to be important to the function of the structurally similar RyR2 (39).…”

Section: Discussionmentioning

confidence: 99%

Propofol directly binds and inhibits skeletal muscle ryanodine receptor 1 (RyR1)

Joseph,

Bu,

Haji-Ghassemi

et al. 2024

Preprint

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As the primary Ca2+ release channel in skeletal muscle sarcoplasmic reticulum (SR), mutations in the type 1 ryanodine receptor (RyR1) or its binding partners underlie a constellation of muscle disorders, including malignant hyperthermia (MH). In patients with MH mutations, exposure to triggering drugs such as the halogenated volatile anesthetics biases RyR1 to an open state, resulting in uncontrolled Ca2+ release, sarcomere tension and heat production. Restoration of Ca2+ into the SR also consumes ATP, generating a further untenable metabolic load. When anesthetizing patients with known MH mutations, the non-triggering intravenous general anesthetic propofol is commonly substituted for triggering anesthetics. While eEvidence of direct binding of anesthetic agents to RyR1 or its binding partners is scant, and the atomic-level interactions of propofol with RyR1 are entirely unknown. Here, we show that propofol decreases RyR1 opening in heavy SR vesicles and planar lipid bilayers, and that it inhibits activator-induced Ca2+ release from SR in human skeletal muscle. In addition to confirming direct binding, photoaffinity labeling using m-azipropofol (AziPm) revealed several putative propofol binding sites on RyR1. Prediction of binding affinity by molecular dynamics simulation suggests that propofol binds at least one of these sites at clinical concentrations. These findings invite the hypothesis that in addition to propofol not triggering MH, it may also be protective against MH by inhibiting induced Ca2+ flux through RyR1.

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Section: Discussionmentioning

confidence: 99%