Anomalous Kv7 channel activity in human malignant hyperthermia syndrome unmasks a key role for H2S and persulfidation in skeletal muscle

Background and Purpose: Human malignant hyperthermia (MH) syndrome is induced by volatile anaesthetics and involves increased levels of cystathionine β-synthase (CBS)-derived H2S within skeletal muscle. This increase contributes to skeletal muscle hypercontractility. Kv7 channels, expressed in skeletal muscle, may be a molecular target for H2S. Here, we have investigated the role of Kv7 channels in MH. Experimental Approach: Skeletal muscle biopsies were obtained from MH-susceptible (MHS) and MH-negative (MHN) patients. Immunohistochemistry, RT-PCR, Western blot, and in vitro contracture test (IVCT) were carried out. Development and characterization of primary human skeletal muscle cells (PHSKMC) and evaluation of cell membrane potential were also performed. The persulfidation state of Kv7 channels and polysulfide levels were measured. Key Results: Kv7 channels were similarly expressed in MHN and MHS biopsies. The IVCT revealed an anomalous contractility of MHS biopsies following exposure to the Kv7 channel opener retigabine. Incubation of negative biopsies with NaHS, prior to retigabine addition, led to an MHS-like positive response. MHS-derived PHSKMC challenged with retigabine showed a paradoxical depolarizing effect, compared with the canonical hyperpolarizing effect. CBS expression and activity were increased in MHS biopsies, resulting in a major polysulfide bioavailability. Persulfidation of Kv7.4 channels was significantly higher in MHS than in MHN biopsies. Conclusions and Implications: In skeletal muscle of MHS patients, CBS-derived H2S induced persulfidation of Kv7 channels. This post-translational modification switches the hyperpolarizing activity into depolarizing. This mechanism can contribute to the pathological skeletal muscle hypercontractility typical of MH syndrome.