Synaptic-like vesicles and candidate transduction channels in mechanosensory terminals

Acknowledgements I would like to thank the Medical Research Council for funding our work from 2007 to 2010 (G0601253), SULSA and Eli Lilly for support to Sonia Watson from 2010 to 2014, and Tenovus Scotland for current support to Karen Thompson.Peer reviewedPublisher PD

Activity-dependent plasticity of transmitter release from nerve terminals in rat fast and slow muscles

Available under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported license.Peer reviewedPublisher PD

Modelling the mechanoreceptor’s dynamic behaviour

All sensory receptors adapt, i.e. they constantly adjust their sensitivity to external stimuli to match the current demands of the natural environment. Electrophysiological responses of sensory receptors from widely different modalities seem to exhibit common features related to adaptation, and these features can be used to examine the underlying sensory transduction mechanisms. Among the principal senses, mechanosensation remains the least understood at the cellular level. To gain greater insights into mechanosensory signalling, we investigated if mechanosensation displayed adaptive dynamics that could be explained by similar biophysical mechanisms in other sensory modalities. To do this, we adapted a fly photoreceptor model to describe the primary transduction process for a stretch-sensitive mechanoreceptor, taking into account the viscoelastic properties of the accessory muscle fibres and the biophysical properties of known mechanosensitive channels (MSCs). The model's output is in remarkable agreement with the electrical properties of a primary ending in an isolated decapsulated spindle; ramp-and-hold stretch evokes a characteristic pattern of potential change, consisting of a large dynamic depolarization during the ramp phase and a smaller static depolarization during the hold phase. The initial dynamic component is likely to be caused by a combination of the mechanical properties of the muscle fibres and a refractory state in the MSCs. Consistent with the literature, the current model predicts that the dynamic component is due to a rapid stress increase during the ramp. More novel predictions from the model are the mechanisms to explain the initial peak in the dynamic component. At the onset of the ramp, all MSCs are sensitive to external stimuli, but as they become refractory (inactivated), fewer MSCs are able to respond to the continuous stretch, causing a sharp decrease after the peak response. The same mechanism could contribute a faster component in the ‘sensory habituation’ of mechanoreceptors, in which a receptor responds more strongly to the first stimulus episode during repetitive stimulation

Importance of Full-Collapse Vesicle Exocytosis for Synaptic Fatigue-Resistance at Rat Fast and Slow Muscle Neuromuscular Junctions

We would like to thank Dr Robert Banks, Prof Arild Njå and Prof Bill Wisden and Dr Phil Sheard for their helpful comments and discussions during the preparation of this manuscript, as well as for the contributions made by undergraduate students Alison Cuthbert, Richard McWilliam and Karen Peters, who helped produce initial observations prompting this study. This work was supported by grants from the Biotechnology and Biological Science Research Council of the UK (BBSRC-1/511921) and The Wellcome Trust (WT-057994/2/99/Z).Peer reviewedPublisher PD

Mechanotransduction channels in proprioceptive sensory nerve terminals: still an open question?

Mechanosensory transduction (MST) in proprioceptors, and other low threshold mechanosensory nerve terminals (LTMT), has been debated intensely for decades. MST in muscle spindles produces a receptor potential that encodes stimulus speed and duration, is predominantly due to Na+, a little Ca2+, plus some transient, non-mechanically-gated K+ ion fluxes. The abundant, multiple Na+-selective DEG/ENaC channel isoforms present in all LTMTs seemed obvious Na+ sources, perhaps supplemented with Ca2+-selective TRPs, and Ca2+-activated K+ channels. However, genetic deletions of even multiple DEG/ENaC genes produces only mild functional perturbation. Conversely, deleting the more recently discovered Piezo2 mechanosensory protein profoundly impairs LTMT responses, including in muscle spindles. Yet, its transient opening, non-Na+-selectivity and pharmacology do not reflect known receptor potential and response properties. A Ca2+-dependent recycling vesicle pool that we have shown is essential for mechanosensitivity, plus other recent DEG/ENaC discoveries, may reconcile these conflicting observations. We propose the abundance of axolemmal MST complexes, comprising untested DEG/ENaC combinations, is controlled by Piezo2-gated Ca2+ influx that regulates their vesicular insertion and retrieval

Development of abnormalities at the neuromuscular junction in the SOD1-G93A mouse model of ALS: dysfunction then disruption of postsynaptic structure precede overt motor symptoms

Introduction: The ultimate deficit in amyotrophic lateral sclerosis (ALS) is neuromuscular junction (NMJ) loss, producing permanent paralysis, ultimately in respiratory muscles. However, understanding the functional and structural deficits at NMJs prior to this loss is crucial for therapeutic strategy design. Should early interventions focus on reversing denervation, or supporting largely intact NMJs that are functionally impaired? We therefore determined when functional and structural deficits appeared in diaphragmatic NMJs relative to the onset of hindlimb tremor (the first overt motor symptoms) in vivo in the SOD1-G93A mouse model of ALS.Materials and methods: We employed electrophysiological recording of NMJ postsynaptic potentials for spontaneous and nerve stimulation-evoked responses. This was correlated with fluorescent imaging microscopy of the postsynaptic acetylcholine receptor (AChR) distribution throughout the postnatal developmental timecourse from 2 weeks to early symptomatic ages.Results: Significant reduction in the amplitudes of spontaneous miniature endplate potentials (mEPPs) and evoked EPPs emerged only at early symptomatic ages (in our colony, 18-22 weeks). Reductions in mEPP frequency, number of vesicles per EPP, and EPP rise time were seen earlier, at 16weeks, but this reversed by early symptomatic ages. However, the earliest and most striking impairment was an inability to maintain EPP amplitude during a 20 Hz stimulus train, which appeared 6 weeks before overt in vivo motor symptoms. Despite this, fluorescent α-bungarotoxin labelling revealed no systematic, progressive changes in 11 comprehensive NMJ morphological parameters (area, shape, compactness, number of acetylcholine receptor, AChR, regions, etc.) with disease progression. Rather, while NMJs were largely normally-shaped, from 16 weeks there was a progressive and substantial disruption in AChR concentration and distribution within the NMJ footprint.Discussion: Thus, NMJ functional deficits appear at least 6 weeks before motor symptoms in vivo, while structural deficits occur 4 weeks later, and predominantly within NMJs. These data suggest initial therapies focused on rectifying suboptimal NMJ function could produce effective relief of symptoms of weakness

Stanniocalcin-2 inhibits skeletal muscle growth and is upregulated in functional overload-induced hypertrophy

ACKNOWLEDGMENTS The authors gratefully acknowledge the Microscopy and Histology Core Facility for their support and assistance in this work. The work presented here was supported as follows. AL: Awards AR052879 and AR056280 from the National Institute of Arthritis, Musculoskeletal and Skin Diseases; award 249156 from the FP7-PEOPLE-2009-RG programme, award CGA/18/05 from the Chief Scientist Office, award 21/019 from the NHS Grampian Research Endowment. AL, GSB and LKH: award 204815/Z/16/Z from the Wellcome Trust. AIHC: The Providence Airway Centre, the St. Paul's Foundation and the Michael Smith Foundation for Health Research trainee award (RT-2021-1591). LKH: Biotechnology and Biological Sciences Research Council (BB/R01857X/1, BB/V016849/1). CO: Independent Research Fund Denmark (201930362460).Peer reviewedPublisher PD

The atypical 'hippocampal' glutamate receptor coupled to phospholipase D that controls stretch-sensitivity in primary mechanosensory nerve endings is homomeric purely metabotropic GluK2

ACKNOWLEDGEMENTS We would like to thank: Prof. Christophe Mulle, University of Bordeaux, France for the generous donation of the GluK2-Neo mice; Prof. Roberto Pellicciari and Prof. Maura Marinozzi, University of Perugia, Italy for the generous gift of PCCG-13; the Microscopy and Histology core facility at the Institute of Medical Sciences, University of Aberdeen for their support and assistance in some of the imaging in this work. We would also like to thank Prof. Gernot Riedel, University of Aberdeen UK and Prof. David Jane, University of Bristol UK for helpful comments during the work and discussion about drafts of this manuscript.Peer reviewedPublisher PD

Piezo is essential for amiloride-sensitive stretch-activated mechanotransduction in larval Drosophila dorsal bipolar dendritic sensory neurons

Date of Acceptance: 05/06/2015Peer reviewedPublisher PD

Patient‐centered digital biomarkers for allergic respiratory diseases and asthma: The ARIA‐EAACI approach – ARIA‐EAACI Task Force Report

Biomarkers for the diagnosis, treatment and follow-up of patients with rhinitis and/ or asthma are urgently needed. Although some biologic biomarkers exist in specialist care for asthma, they cannot be largely used in primary care. There are no validated biomarkers in rhinitis or allergen immunotherapy (AIT) that can be used in clinical practice. The digital transformation of health and health care (including mHealth) places the patient at the center of the health system and is likely to optimize the practice of allergy. Allergic Rhinitis and its Impact on Asthma (ARIA) and EAACI (European Academy of Allergy and Clinical Immunology) developed a Task Force aimed at proposing patient-reported outcome measures (PROMs) as digital biomarkers that can be easily used for different purposes in rhinitis and asthma. It first defined control digital biomarkers that should make a bridge between clinical practice, randomized controlled trials, observational real-life studies and allergen challenges. Using the MASK-air app as a model, a daily electronic combined symptom-medication score for allergic diseases (CSMS) or for asthma (e-DASTHMA), combined with a monthly control questionnaire, was embedded in a strategy similar to the diabetes approach for disease control. To mimic real-life, it secondly proposed quality-of- life digital biomarkers including daily EQ-5D visual analogue scales and the bi-weekly RhinAsthma Patient Perspective (RAAP). The potential implications for the management of allergic respiratory diseases were proposed.info:eu-repo/semantics/publishedVersio