Anomalous K 7 channel activity in human malignant hyperthermia syndrome unmasks a key role for H S 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 H S within skeletal muscle. This increase contributes to skeletal muscle hypercontractility. K 7 channels, expressed in skeletal muscle, may be a molecular target for H S. Here, we have investigated the role of K 7 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 K 7 channels and polysulfide levels were measured.

KEY RESULTS

K 7 channels were similarly expressed in MHN and MHS biopsies. The IVCT revealed an anomalous contractility of MHS biopsies following exposure to the K 7 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 K 7.4 channels was significantly higher in MHS than in MHN biopsies.

CONCLUSIONS AND IMPLICATIONS

In skeletal muscle of MHS patients, CBS-derived H S induced persulfidation of K 7 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.

LINKED ARTICLES

This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.

© 2019 The British Pharmacological Society.