It is often unclear why some genetic mutations to a given gene contribute to neurological disorders and others do not. For instance, two mutations have previously been found to produce a dominant ...negative for TRESK, a two-pore-domain K+ channel implicated in migraine: TRESK-MT, a 2-bp frameshift mutation, and TRESK-C110R. Both mutants inhibit TRESK, but only TRESK-MT increases sensory neuron excitability and is linked to migraine. Here, we identify a new mechanism, termed frameshift mutation-induced alternative translation initiation (fsATI), that may explain why only TRESK-MT is associated with migraine. fsATI leads to the production of a second protein fragment, TRESK-MT2, which co-assembles with and inhibits TREK1 and TREK2, two other two-pore-domain K+ channels, to increase trigeminal sensory neuron excitability, leading to a migraine-like phenotype in rodents. These findings identify TREK1 and TREK2 as potential molecular targets in migraine and suggest that fsATI should be considered as a distinct class of mutations.
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•TRESK, a K2P channel implicated in migraine, heteromerizes with TREK1 and TREK2•Migraine-associated TRESK-MT mutant induces formation of two proteins: MT1 and MT2•MT2 is produced by frameshift mutation-induced alternative translation initiation•MT2 inhibits TREK to increase neuronal excitability and induce a migraine phenotype
Royal et al. demonstrate that migraine-associated frameshift mutations of TRESK, a two-pore-domain K+ channel, lead to the production of a second protein fragment, which carries the pathophysiological function by inhibiting TREK1 and 2, due to a mechanism called frameshift mutation-induced alternative translation initiation (fsATI).
In this issue of Neuron, Kanda et al. (2019) find that the two-pore domain potassium channels TRAAK and TREK1 drive axonal action potential repolarization for high-speed and high-frequency nervous ...impulses in mammalian myelinated nerves.
In this issue of Neuron, Kanda et al. (2019) find that the two-pore domain potassium channels TRAAK and TREK1 drive axonal action potential repolarization for high-speed and high-frequency nervous impulses in mammalian myelinated nerves.
•TREK channels are involved in pain perception.•TREK channel heteromerization is involved in migraine.•TREK channels regulate sensory neuron excitability.•TREK channels as targets for pain and ...migraine treatment.
The ability to sense pain signals is closely linked to the activity of ion channels expressed in nociceptors, the first neurons that transduce noxious stimuli into pain. Among these ion channels, TREK1, TREK2 and TRAAK from the TREK subfamily of the Two-Pore-Domain potassium (K2P) channels, are hyperpolarizing channels that render neurons hypoexcitable. They are regulated by diverse physical and chemical stimuli as well as neurotransmitters through G-protein coupled receptor activation. Here, we review the molecular mechanisms underlying these regulations and their functional relevance in pain and migraine induction.
Determination of what is the specificity of subunits composing a protein complex is essential when studying gene variants on human pathophysiology. The pore-forming α-subunit KCNQ1, which belongs to ...the voltage-gated ion channel superfamily, associates to its β-auxiliary subunit KCNE1 to generate the slow cardiac potassium IKs current, whose dysfunction leads to cardiac arrhythmia. Using pharmacology, gene invalidation, and single-molecule fluorescence assays, we found that KCNE1 fulfils all criteria of a bona fide auxiliary subunit of the TMEM16A chloride channel, which belongs to the anoctamin superfamily. Strikingly, assembly with KCNE1 switches TMEM16A from a calcium-dependent to a voltage-dependent ion channel. Importantly, clinically relevant inherited mutations within the TMEM16A-regulating domain of KCNE1 abolish the TMEM16A modulation, suggesting that the TMEM16A-KCNE1 current may contribute to inherited pathologies. Altogether, these findings challenge the dogma of the specificity of auxiliary subunits regarding protein complexes and questions ion channel classification.
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•KCNE1 can serve as an auxiliary subunit of two superfamilies of ion channels•KCNE1 is an auxiliary subunit of the TMEM16A chloride channel•TMEM16A-KCNE1 channel mediates a voltage-gated Cl− current independently of Ca2+•KCNE1 S38G and R32H polymorphisms abolish the KCNE1-TMEM16A Cl− current
KCNE1, a β-subunit of the cardiac KCNQ1 channel belonging to the voltage-dependent channel superfamily, serves also as an auxiliary subunit of the anoctamin superfamily member TMEM16A, a calcium-activated chloride channel. By interacting with TMEM16A, KCNE1 induces a voltage-dependent current in the absence of intracellular calcium elevation dynamically regulated by angiotensin II in native tissue.
Migraine and Two-Pore-Domain Potassium Channels Verkest, Clément; Häfner, Stephanie; Ávalos Prado, Pablo ...
The Neuroscientist,
06/2021, Letnik:
27, Številka:
3
Book Review, Journal Article
Recenzirano
Odprti dostop
Migraine is a common, disabling neurological disorder with a genetic, environmental, and hormonal component with an annual prevalence estimated at ~15%. It is characterized by attacks of severe, ...usually unilateral and throbbing headache, and can be accompanied by nausea, vomiting, and photophobia. Migraine is clinically divided into two main subtypes: migraine with aura, when it is preceded by transient neurological disturbances due to cortical spreading depression (CSD), and migraine without aura. Activation and sensitization of trigeminal sensory neurons, leading to the release of pro-inflammatory peptides, is likely a key component in headache pain initiation and transmission in migraine. In the present review, we will focus on the function of two-pore-domain potassium (K2P) channels, which control trigeminal sensory neuron excitability and their potential interest for developing new drugs to treat migraine.
Since the governments of Chile, Colombia, Mexico, and Peru inaugurated a new Latin American integration mechanism, the Pacific Alliance, in 2011, the bloc has recorded both encouraging and ...disappointing results, depending on the evolution of the Alliance's main five aspects—political, economic, institutional, cooperative, and societal linkages. Although economic integration did not advance at the expected pace, owing to the abolition of a Mexican visa for Peru and Colombia, between 2011 and 2019, there has been a significant increase in social exchanges of nationals of the four countries, which included activities such as tourism, education, business trips, and others of similar nature (the Pacific Alliance's fifth element). Yet, despite these developments, scholars did not attempt to examine the societal linkage within the bloc, referred to in this article as the “fifth element” of the Pacific Alliance. To narrow the gap, this article examines the path of the Alliance toward deep integration by identifying the effect of strengthening social interactions, using a transnationalist framework and paying particular attention to the changing patterns of individual trips over more than 10 years of the Alliance's existence.
Desde que en el año 2011 los gobiernos de Chile, Colombia, México y Perú crearon a la Alianza del Pacífico, como un nuevo mecanismo de integración latinoamericana, el bloque ha registrado resultados tanto alentadores como decepcionantes, en función del estado de los cinco principales pilares que la conforman: el político, el económico, su estructura institucional, la cooperación y la vinculación social entre los nacionales de los países miembros. Si bien la integración económica no ha avanzado al ritmo esperado, entre 2011 y 2019 en el seno de la Alianza se produjeron importantes intercambios societales entre los países miembros, que incluyeron turismo, educación, viajes de negocios, y otros, cuyos flujos muestran un incremento significativo. Sin embargo, a pesar de esta dinámica, este rubro del mecanismo latinoamericano no ha sido suficientemente analizado, el cual este artículo aborda y lo conceptualiza como el “quinto elemento” de la Alianza del Pacífico. Para ello, mediante el marco teórico transnacional, el artículo examina el camino de la Alianza hacia una integración profunda mediante la identificación de interacciones sociales representativas entre los países integrantes durante diez años.
自智利、哥伦比亚、墨西哥和秘鲁政府于 2011 年启动新的拉美一体化机制——太平洋联盟以来，该联盟已取得了一系列成就与失败，这取决于联盟在政治联系、经济联系 、制度联系、合作联系和社会联系这五个主要方面的进展。尽管经济一体化没有以预期的速度推进，但由于墨西哥对秘鲁和哥伦比亚取消了签证要求，在2011 年至 2019 年期间，这四个国家的国民社会交流，包括旅游、教育、商务旅行等活动，和其他类似性质的活动（即太平洋联盟的第五要素）都出现显著增长。不过，尽管存在这些发展，学者并未试图分析该集团内部的社会联系（本文将其称为太平洋联盟的“第五要素”）。 为填补该研究空白距，本文通过识别“加强社会互动”一事产生的影响，以分析太平洋联盟的深度一体化路径。本文使用一项跨国主义框架，特别聚焦于联盟成立 10 多年来个人旅行模式的变化。
Nature-conservation practices in the Global South are fraught with uncertainty due to fragile environmental governance and conflict stemming from their subaltern position in global capitalism, given ...the tension between human needs and habitat integrity. This article hinges on a recent effort spear-headed by the Centre of Conservation Studies at University of San Carlos in Guatemala, to discuss how a counterhegemonic narrative offers fertile grounds for a decolonized reading of the metabolic rift. I use my notes from eight workshops held in 2018 as the empirical body for a discourse analysis where the emerging categories have been singled out and problematized in the light of ethnoecological theory and David Harvey’s moments for the transition towards a post-Capitalist society vis-à-vis a prevailing environmental regime characterized by its verticality, lack of scientific substantiation, and proclivity to privilege exchange value at the expense of widening the metabolic rift. This regime arguably spawns several ecological rifts, namely the following: (1) between conventional scientific parlance and traditional ecological knowledge; (2) between utility-inspired natural resource management and local land husbandry practices; and (3) between nature as a reservoir of resources and nature as the sustenance for life. In addition, I present a case study where local advocacy in a peripheral community managed to bring about a relevant shift in the correlation of political powers by seizing the national legislation to achieve a transfer of property rights that enabled the inception of a brand-new nature reserve. The new conservation paradigm in question, this case seems to suggest, dovetails adequately with civil society’s efforts to foster nature-conservation practices, in line with human well-being and sound environmental governance. The latter provides some evidence for a principle of hope – à la Ernst Bloch – whereby, dissident groups are paving the way for a grassroots-oriented conservation science that eventually could bridge the metabolic rift.
Purpose
To assess feasibility and accuracy of point‐of‐care (POC) NMR‐proton density fat fraction (PDFF) in phantoms and in a human pilot study in a POC setting.
Methods
POC NMR (LiverScope, Livivos, ...San Diego CA) PDFF measurements were obtained of certified phantoms with known PDFF values (0%‐40%). In an institutional review board‐approved, Health Insurance Portability and Accountability Act‐compliant prospective human study, a convenience sample of participants from an obesity clinic was enrolled (November 2020 to June 2021). The inclusion criteria required body mass index (BMI) = 27‐40 kg/m2 and willingness to undergo POC NMR and MRI‐PDFF measurements. Liver PDFF was measured by POC NMR and, within 35 days after, by a confounder corrected CSE MRI PDFF acquisition and reconstruction method. The adverse events were documented and linear regression analyses were performed.
Results
POC NMR‐PDFF measurements agreed with known phantom PDFF values (R2 = 0.99). Fourteen participants were enrolled in the pilot human study. MRI‐PDFF could not be obtained in 4 participants (claustrophobia reaction, n = 3, exceeded size of MR scanner bore, n = 1). POC NMR was unevaluable in 2 participants (insufficient signal penetration depth, n = 1, failure to comply with instructions, n = 1). Technical success was 11 of 13 (85%) for POC NMR PDFF. In 7 participants (4 female; 31‐74 years old; median BMI 35 kg/m2), MRI‐PDFF (range, 2.8%‐18.1%), and POC NMR‐PDFF (range, 3%‐25.2%), agreed with R2 = 0.94. POC NMR had no adverse events.
Conclusion
POC NMR measures PDFF accurately in phantoms and, in a first‐in‐human pilot study, is feasible and accurate in adults with obesity. Further testing to determine precision and accuracy across larger and more diverse cohorts is needed.
Introduction. Food packaging has played an important and varied role, accordance with the requirements and demands of the market. Currently, these needs are focused on the goal of having safe and ...innocuous food for as long as possible. To this end, the study and development of new technologies for food packaging has been expanded, which provides the conditions and characteristics necessary to achieve the proposed objective. Objective. To present the most recent advances in the field of food packaging (active and intelligent). Development. This work presents different techniques and criteria that are considered used to propose the concept of active packaging. Gathering the necessary conditions for the supply or suppression of beneficial or harmful substances, contributing to the conservation and deterioration of the contained foods. In some cases, various compounds, mostly of natural origin, are incorporated to counteract the deterioration of food, such as antioxidants, antimicrobials, oxygen absorbers, carbon dioxide, and ethylene. At the same time, the technology known as intelligent packaging is presented, equipped with the necessary resources to monitor and interpret the internal state of the container, and with the ability to communicate this condition visually to be identified by consumers, merchants, and manufacturers. In both cases, the aim is to eliminate or delay the undesirable modification of food and its implications for human health. Conclusions. The generation of active and intelligent packaging represents an important innovation, which manages to increase the shelf life of food, in conditions suitable for consumption. Reaching a considerable economic impact of the sectors involved. These new developments require an individual evaluation of each specific food against the components used. To know the concentrations, according to the characteristic that is required to be controlled, and in this way, understand the possible interactions that can occur between the content and the container that contains it.
Introducción. El envasado de alimentos ha jugado un papel importante y variado, de acuerdo con los requerimientos y demandas del mercado. Actualmente, estas necesidades se centran en el objetivo de tener alimentos seguros e inocuos durante el mayor tiempo posible. Para ello, se ha ampliado el estudio y desarrollo de nuevas tecnologías para el envasado de alimentos, que aportan las condiciones y características necesarias para conseguir el objetivo propuesto. Objetivo. Presentar los avances más recientes en el campo de los envases para alimentos (activos e inteligentes). Desarrollo. Este trabajo presenta diferentes técnicas y criterios que se consideran utilizados para proponer el concepto de envase activo. Reuniendo las condiciones necesarias para el suministro o supresión de sustancias benéficas o dañinas, contribuyendo a la conservación y deterioro de los alimentos contenidos. En algunos casos, se incorporan diversos compuestos, en su mayoría de origen natural, para contrarrestar el deterioro de los alimentos como es el caso de antioxidantes, antimicrobianos, absorbedores de oxígeno, dióxido de carbono y etileno. Además, se presenta la tecnología conocida como embalaje inteligente, dotado de los recursos necesarios para monitorizar e interpretar el estado interno del envase, y con la capacidad de comunicar esta condición de manera visual para ser identificado por los consumidores, comerciante y fabricantes. En ambos casos, se busca eliminar o retardar la modificación indeseada de los alimentos y sus implicaciones sobre la salud humana. Conclusiones. La generación de envases activos e inteligentes representa una importante innovación, que logra incrementar la vida útil de los alimentos, en condiciones aptas para su consumo. Alcanzando un considerable impacto económico de los sectores involucrados. Estos nuevos desarrollos requieren una evaluación individual de cada alimento específico frente a los componentes utilizados. Para conocer las concentraciones, según la característica que se requiera controlar, y de este modo, comprender las posibles interacciones que pueden ocurrir entre el contenido y el recipiente que lo contiene.
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