Anomalous Kv 7 channel activity in human malignant hyperthermia syndrome unmasks a key role for H2 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 ß-synthase (CBS)-derived H2 S within skeletal muscle. This increase contributes to skeletal muscle hypercontractility. Kv 7 channels, expressed in skeletal muscle, may be a molecular target for H2 S. Here, we have investigated the role of Kv 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 Kv 7 channels and polysulfide levels were measured. KEY RESULTS: Kv 7 channels were similarly expressed in MHN and MHS biopsies. The IVCT revealed an anomalous contractility of MHS biopsies following exposure to the Kv 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 Kv 7.4 channels was significantly higher in MHS than in MHN biopsies. CONCLUSIONS AND IMPLICATIONS: In skeletal muscle of MHS patients, CBS-derived H2 S induced persulfidation of Kv 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.

Attentional biases for threat after fear-related autobiographical recall.

BACKGROUND: Previous studies suggested that affective state could enhance stimulus salience and modulate attention allocation for mood-congruent information, but contrasting data have been reported on the effects of mood induction on attentional biases for threat (ABTs) in non-clinical individuals. OBJECTIVE: We aimed to assess whether laboratory-induced negative mood can increase individuals' tendency to allocate attention on threatening stimuli, thus determining a difficulty in attentional disengagement from threat. We also aimed at assessing whether level of trait anxiety could modulate the effect of mood induction on attentional biases. METHODS: We used an autobiographical episode recall procedure for mood induction (fear, happiness and neutral episode recall), and an exogenous cueing task with threatening and non-threatening images to assess attentional biases in 120 undergraduate students. RESULTS: Participants showed a significant difficulty in disengaging attention from threat after recalling fear-related episodes, independently from their trait anxiety level. CONCLUSIONS: These findings clarify that the ABTs are not exclusive to anxiety disorders or high trait anxiety individuals, and could also arise in non-clinical individuals in a fearful context.