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

被引：16

作者：

Vellecco, Valentina ^{[1
]}

Martelli, Alma ^{[2
]}

Bibli, Iris Sofia ^{[3
,4
]}

Vallifuoco, Marianna ^{[5
]}

Manzo, Onorina L. ^{[1
]}

Panza, Elisabetta ^{[1
]}

Citi, Valentina ^{[2
]}

Calderone, Vincenzo ^{[2
]}

De Dominicis, Gianfranco ^{[6
]}

Cozzolino, Caterina ^{[6
]}

Basso, Elisabetta M. ^{[5
]}

Mariniello, Martina ^{[5
]}

Fleming, Ingrid ^{[3
,4
]}

Mancini, Antonio ^{[5
]}

Bucci, Mariarosaria ^{[1
]}

Cirino, Giuseppe ^{[1
]}

机构：

[1] Univ Naples Federico II, Sch Med, Dept Pharm, Via Domenico Montesano 49, I-80131 Naples, Italy

[2] Univ Pisa, Dept Pharm, Pisa, Italy

[3] Goethe Univ Frankfurt Main, Inst Vasc Signalling, Ctr Mol Med, Frankfurt, Germany

[4] German Ctr Cardiovasc Res DZHK, Partner Site RheinMain, Frankfurt, Germany

[5] A Cardarelli Hosp, Ctr Biotechnol, Naples, Italy

[6] A Cardarelli Hosp, UOSC, Pathol Anat, Naples, Italy

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2020年 / 177卷 / 04期

关键词：

CYSTATHIONINE-BETA-SYNTHASE; HYDROGEN-SULFIDE; POTASSIUM CHANNELS; CONCISE GUIDE; DIFFERENTIATION; PHARMACOLOGY; SUSCEPTIBILITY; INHIBITION; ACTIVATION; PROLIFERATION;

D O I：

10.1111/bph.14700

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Background and Purpose Human malignant hyperthermia (MH) syndrome is induced by volatile anaesthetics and involves increased levels of cystathionine beta-synthase (CBS)-derived H2S within skeletal muscle. This increase contributes to skeletal muscle hypercontractility. K(v)7 channels, expressed in skeletal muscle, may be a molecular target for H2S. Here, we have investigated the role of K(v)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(v)7 channels and polysulfide levels were measured. Key Results K(v)7 channels were similarly expressed in MHN and MHS biopsies. The IVCT revealed an anomalous contractility of MHS biopsies following exposure to the K(v)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(v)7.4 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 K(v)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

引用

页码：810 / 823

页数：14