Search

TWIK-related K + channel (TREK-1) two-pore-domain potassium (K 2P ) channels mediate background potassium currents and regulate cellular excitability in many different types of cells. Their functional activity is controlled by a broad variety of different physiological stimuli, such as temperature, extracellular or intracellular pH, lipids and mechanical stress. By linking cellular excitability to mechanical stress, TREK-1 currents might be important to mediate parts of the mechanoelectrical feedback described in the heart. Furthermore, TREK-1 currents might contribute to the dysregulation of excitability in the heart in pathophysiological situations, such as those caused by abnormal stretch or ischaemia-associated cell swelling, thereby contributing to arrhythmogenesis. In this review, we focus on the functional role of TREK-1 in the heart and its putative contribution to cardiac mechanoelectrical coupling. Its cardiac expression among different species is discussed, alongside with functional evidence for TREK-1 currents in cardiomyocytes. In addition, evidence for the involvement of TREK-1 currents in different cardiac arrhythmias, such as atrial fibrillation or ventricular tachycardia, is summarized. Furthermore, the role of TREK-1 and its interaction partners in the regulation of the cardiac heart rate is reviewed. Finally, we focus on the significance of TREK-1 in the development of cardiac hypertrophy, cardiac fibrosis and heart failure., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could be perceived to have influenced the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene., Methods: We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK-1 current., Results: We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy-terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands' muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice-site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano-gated potassium channel, TREK-1., Interpretation: Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832-843., (© 2019 American Neurological Association.)

Two-pore-domain potassium (K 2P ) channels are key regulators of many physiological and pathophysiological processes and thus emerged as promising drug targets. As for other potassium channels, there is a lack of selective blockers, since drugs preferentially bind to a conserved binding site located in the central cavity. Thus, there is a high medical need to identify novel drug-binding sites outside the conserved lipophilic central cavity and to identify new allosteric mechanisms of channel inhibition. Here, we identified a novel binding site and allosteric inhibition mechanism, disrupting the recently proposed K + -flux gating mechanism of K 2P channels, which results in an unusual voltage-dependent block of leak channels belonging to the TASK subfamily. The new binding site and allosteric mechanism of inhibition provide structural and mechanistic insights into the gating of TASK channels and the basis for the drug design of a new class of potent blockers targeting specific types of K 2P channels., Competing Interests: SR, AK, KV, DR, MS, MB, DA, IG, MN, PS, TB, WG, ND No competing interests declared, (© 2019, Rinné et al.)