scholarly journals Chemical Gating of the Mechanosensitive Piezo1 Channel by Asymmetric Binding of its Agonist Yoda1

2017 ◽  
Author(s):  
Jerome J. Lacroix ◽  
Wesley M. Botello-Smith ◽  
Yun Luo
Keyword(s):  
Chemical Activation ◽  
Gating Mechanisms ◽  
Channel Opening ◽  
Chemical Gating ◽  
Piezo Channels ◽  
Single Subunit ◽  
Therapeutic Avenue ◽  
Shed Light ◽  
Minimal Region ◽  
Pharmacological Control

AbstractPiezo proteins are homotrimeric ion channels that play major roles in normal and pathological mechanotransduction signaling in mammalian organisms. Their pharmacological control hence represents a potential therapeutic avenue. Yoda1, a Piezo1-selective small molecule agonist, is the only known selective Piezo modulator. How Yoda1 selectively interacts with Piezo1 and opens its pore is unknown. Here, by engineering and characterizing chimeras, we identified a minimal region responsible for Yoda1 binding. This region is located at the interface between the pore and the putative mechanosensory domains in each subunit. By characterizing hybrid channels containing Yoda1-insensitive and Yoda1-sensitive monomers, we demonstrate that the presence of only one Yoda1-sensitive Piezo1 subunit is sufficient for chemical activation, implicating that the asymmetric binding of Yoda1 to a single subunit enables channel opening. These findings shed light onto the gating mechanisms of Piezo channels and will pave the way for the rationale design of new Piezo channels modulators.

Unusual relatives of the multisubunit RNA polymerase

2018 ◽  
Vol 47 (1) ◽  
pp. 219-228 ◽  
Author(s):  
David Forrest
Keyword(s):  
Gene Expression ◽  
Bacillus Subtilis ◽  
Rna Polymerase ◽  
Kluyveromyces Lactis ◽  
Current Understanding ◽  
Magnesium Binding ◽  
Killer System ◽  
Domains Of Life ◽  
Single Subunit ◽  
Shed Light

AbstractTranscription, the first step of gene expression, is accomplished in all domains of life by the multisubunit RNA polymerase (msRNAP). Accordingly, the msRNAP is an ancient enzyme that is ubiquitous across all cellular organisms. Conserved in absolutely all msRNAPs is the catalytic magnesium-binding aspartate triad and the structural fold it is present on, the double ψ β barrel (DPBB). In-depth bioinformatics has begun to reveal a wealth of unusual proteins distantly related to msRNAP, identified due to their possession of the aspartate triad and DPBB folds. Three examples of these novel RNAPs are YonO of the Bacillus subtilis SPβ prophage, non-virion RNAP (nvRNAP) of the B. subtilis AR9 bacteriophage and ORF6 RNAP of the Kluyveromyces lactis cytoplasmic killer system. While YonO and AR9 nvRNAP are both bacteriophage enzymes, they drastically contrast. YonO is an incredibly minimal single-subunit RNAP, while AR9 nvRNAP is multisubunit bearing much more resemblance to the canonical msRNAP. ORF6 RNAP is an intermediate, given it is a single-subunit enzyme with substantial conservation with the msRNAP. Recent findings have begun to shed light on these polymerases, which have the potential to update our understanding of the mechanisms used for transcription and give new insights into the canonical msRNAP and its evolution. This mini-review serves to introduce and outline our current understanding of these three examples of novel, unusual RNAPs.

scholarly journals Independence and Cooperativity in Rearrangements of a Potassium Channel Voltage Sensor Revealed by Single Subunit Fluorescence

2000 ◽  
Vol 115 (3) ◽  
pp. 257-268 ◽  
Author(s):  
Lidia M. Mannuzzu ◽  
Ehud Y. Isacoff
Keyword(s):  
Action Potential ◽  
Potassium Channel ◽  
Voltage Gated ◽  
Channel Opening ◽  
Physiological Relevance ◽  
Voltage Dependent ◽  
Action Potential Threshold ◽  
Single Subunit ◽  
S4 Segment ◽  
Potential Threshold

Voltage-gated potassium channels are composed of four subunits. Voltage-dependent activation of these channels consists of a depolarization-triggered series of charge-carrying steps that occur in each subunit. These major charge-carrying steps are followed by cooperative step(s) that lead to channel opening. Unlike the late cooperative steps, the major charge-carrying steps have been proposed to occur independently in each of the channel subunits. In this paper, we examine this further. We showed earlier that the two major charge-carrying steps are associated with two sequential outward transmembrane movements of the charged S4 segment. We now use voltage clamp fluorometry to monitor these S4 movements in individual subunits of heterotetrameric channels. In this way, we estimate the influence of one subunit's S4 movement on another's when the energetics of their transmembrane movements differ. Our results show that the first S4 movement occurs independently in each subunit, while the second occurs cooperatively. At least part of the cooperativity appears to be intrinsic to the second S4 charge-carrying rearrangement. Such cooperativity in gating of voltage-dependent channels has great physiological relevance since it can affect both action potential threshold and rate of propagation.

scholarly journals Activated carbons by zinc chloride activation for dye removal – a commentary

2018 ◽  
Vol 11 (2) ◽  
pp. 99-106 ◽  
Author(s):  
Pua Eng Hock ◽  
Muhammad Abbas Ahmad Zaini
Keyword(s):  
Activated Carbon ◽  
Zinc Chloride ◽  
Activated Carbons ◽  
Chemical Activation ◽  
Operating Conditions ◽  
Factors Affecting ◽  
Adsorption Of Water ◽  
And Performance ◽  
Insight Into ◽  
Shed Light

Abstract Zinc chloride is a commonly used activator in chemical activation of activated carbon. Various carbonaceous materials have been studied as potential source of activated carbon. The operating conditions are manipulated with attention to improve the properties and performance of activated carbon in the adsorption of water pollutants. However, the generalized attributes of zinc chloride activation in relation to the adsorptive performance of activated carbon are not well documented in much of published literature. Therefore, the present work is aimed to highlight the activation strategies and mechanisms of zinc chloride activation of activated carbon. The roles of impregnation ratio, period of activation and temperature are discussed to offer some insight into textural characteristics of activated carbon. The case studies on methylene blue adsorption are integrated to shed light on the external factors affecting the adsorption.

scholarly journals TRPV1 activation relies on hydration/dehydration of nonpolar cavities

2017 ◽  
Author(s):  
Marina A. Kasimova ◽  
Aysenur Yazici ◽  
Yevgen Yudin ◽  
Daniele Granata ◽  
Michael L. Klein ◽  
...  
Keyword(s):  
Free Energy ◽  
High Temperature ◽  
Low Ph ◽  
Free Energy Calculations ◽  
Side Chain ◽  
Temperature Dependent ◽  
Gating Mechanisms ◽  
Evolutionarily Conserved ◽  
Central Pore ◽  
Shed Light

ABSTRACTTRPV1 promotes cationic currents across cellular membranes in response to multiple stimuli such as increased temperature, binding of chemicals, low pH and voltage. The molecular underpinnings of TRPV1 gating, in particular the mechanism of temperature sensitivity, are still largely unknown. Here, we used molecular simulations and electrophysiology to shed light on the closed to open transition. Specifically, we found that gating of TRPV1 relies on the motion of an evolutionarily conserved amino acid (N676) in the middle of the S6 helix. On rotation, the side chain of this asparagine faces either the central pore or the S4-S5 linker. Only in the former case is the central pore hydrated and thus conductive. Interestingly, when N676 rotates toward the linker, we observe hydration of four so far unreported small nonpolar cavities. Based on these findings, we propose a model for TRPV1 gating involving the dynamic hydration of these four cavities. Free energy calculations indicate that this gating mechanisms is markedly temperature dependent favoring the open state at high temperature. On the basis of this model, which is able to rationalize a wealth of seemingly conflicting and/or unrelated experimental observations, we predicted the behavior of two single residue mutants, M572A and F580Y, the consequences of which we confirmed experimentally.

Elucidating cyclic AMP signaling in subcellular domains with optogenetic tools and fluorescent biosensors

2019 ◽  
Vol 47 (6) ◽  
pp. 1733-1747 ◽  
Author(s):  
Christina Klausen ◽  
Fabian Kaiser ◽  
Birthe Stüven ◽  
Jan N. Hansen ◽  
Dagmar Wachten
Keyword(s):  
Cyclic Amp ◽  
Adenosine Monophosphate ◽  
Adenylyl Cyclases ◽  
Temporal Precision ◽  
Fluorescent Biosensors ◽  
Subcellular Domains ◽  
Spatio Temporal ◽  
Hydrolysis Of ◽  
Shed Light ◽  
Cyclic Amp Signaling

The second messenger 3′,5′-cyclic nucleoside adenosine monophosphate (cAMP) plays a key role in signal transduction across prokaryotes and eukaryotes. Cyclic AMP signaling is compartmentalized into microdomains to fulfil specific functions. To define the function of cAMP within these microdomains, signaling needs to be analyzed with spatio-temporal precision. To this end, optogenetic approaches and genetically encoded fluorescent biosensors are particularly well suited. Synthesis and hydrolysis of cAMP can be directly manipulated by photoactivated adenylyl cyclases (PACs) and light-regulated phosphodiesterases (PDEs), respectively. In addition, many biosensors have been designed to spatially and temporarily resolve cAMP dynamics in the cell. This review provides an overview about optogenetic tools and biosensors to shed light on the subcellular organization of cAMP signaling.

Sentence-Based Experience Logging in New Hearing Aid Users

2020 ◽  
Vol 29 (3S) ◽  
pp. 631-637
Author(s):  
Katja Lund ◽  
Rodrigo Ordoñez ◽  
Jens Bo Nielsen ◽  
Dorte Hammershøi
Keyword(s):  
Hearing Aid ◽  
Patient Experiences ◽  
Online Tool ◽  
Rehabilitation Process ◽  
Hearing Rehabilitation ◽  
Clinical Observations ◽  
Hearing Aid Use ◽  
Wide Range ◽  
Insight Into ◽  
Shed Light

Purpose The aim of this study was to develop a tool to gain insight into the daily experiences of new hearing aid users and to shed light on aspects of aided performance that may not be unveiled through standard questionnaires. Method The tool is developed based on clinical observations, patient experiences, expert involvement, and existing validated hearing rehabilitation questionnaires. Results An online tool for collecting data related to hearing aid use was developed. The tool is based on 453 prefabricated sentences representing experiences within 13 categories related to hearing aid use. Conclusions The tool has the potential to reflect a wide range of individual experiences with hearing aid use, including auditory and nonauditory aspects. These experiences may hold important knowledge for both the patient and the professional in the hearing rehabilitation process.

Inherited Disorders Shed Light on Desmosomes

2006 ◽  
Vol 37 (11) ◽  
pp. 42
Author(s):  
KERRI WACHTER
Keyword(s):  
Inherited Disorders ◽  
Shed Light

Careful Dx Can Shed Light on Trio of Photosensitivity Diseases

2005 ◽  
Vol 36 (4) ◽  
pp. 26
Author(s):  
KATE JOHNSON
Keyword(s):  
Shed Light

Pearls Shed Light on Tx for Dark-Skinned Children

2006 ◽  
Vol 37 (4) ◽  
pp. 42
Author(s):  
HEIDI SPLETE
Keyword(s):  
Shed Light

The Role of Zinc in Thyroid Hormones Metabolism

2019 ◽  
Vol 89 (1-2) ◽  
pp. 80-88 ◽  
Author(s):  
Juliana Soares Severo ◽  
Jennifer Beatriz Silva Morais ◽  
Taynáh Emannuelle Coelho de Freitas ◽  
Ana Letícia Pereira Andrade ◽  
Mayara Monte Feitosa ◽  
...  
Keyword(s):  
Thyroid Hormones ◽  
Scientific Evidence ◽  
Thyroid Stimulating Hormone ◽  
Zinc Transporters ◽  
Serum Concentrations ◽  
Metabolic Adaptations ◽  
Serum T3 ◽  
Regulatory Effects ◽  
Shed Light

Abstract. Thyroid hormones play an important role in body homeostasis by facilitating metabolism of lipids and glucose, regulating metabolic adaptations, responding to changes in energy intake, and controlling thermogenesis. Proper metabolism and action of these hormones requires the participation of various nutrients. Among them is zinc, whose interaction with thyroid hormones is complex. It is known to regulate both the synthesis and mechanism of action of these hormones. In the present review, we aim to shed light on the regulatory effects of zinc on thyroid hormones. Scientific evidence shows that zinc plays a key role in the metabolism of thyroid hormones, specifically by regulating deiodinases enzymes activity, thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH) synthesis, as well as by modulating the structures of essential transcription factors involved in the synthesis of thyroid hormones. Serum concentrations of zinc also appear to influence the levels of serum T3, T4 and TSH. In addition, studies have shown that Zinc transporters (ZnTs) are present in the hypothalamus, pituitary and thyroid, but their functions remain unknown. Therefore, it is important to further investigate the roles of zinc in regulation of thyroid hormones metabolism, and their importance in the treatment of several diseases associated with thyroid gland dysfunction.

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