Biology subjects

Smart, T.

Publications and source records attributed to Smart, T..

3 recordsLinked to original sources

bioRxiv2023

Sex disparities in age-related neuromuscular decline: unveiling female susceptibility from early to late elderly

BackgroundFemales typically have a longer lifespan than males which is not matched by an improved healthspan, with older females having higher rates of frailty, characteristic of a sex specific degradation of the neuromuscular system. Several motor unit (MU) characteristics show sex-specific behaviour during mid-level contractions in healthy younger people, highlighting a potential influence of hormonal differences that may be augmented in older age. The purpose of this study was to investigate sex differences in physical performance and MU features of the aged human vastus lateralis (VL) from early to late elderly. MethodsThis study included 21 healthy older males (mean {+/-} SD, range: 67.2 {+/-} 7.6, 56 - 81 yrs) and 17 healthy older females (69.5 {+/-} 5.2, 60 - 78 yrs). Intramuscular electromyography data were collected from VL during standardised submaximal sustained contractions. Muscle size and physical performance characteristics were also measured. Multiple mixed-effects linear regression models with age considered were conducted and statistical significance was accepted when p<0.05. ResultsWhen compared to males, early to late elderly females had smaller cross-sectional area of VL (p<0.001), lower knee extensor torque (p<0.001) and poorer force steadiness (p=0.036), as well as higher MU firing rate (FR) (p=0.025) and greater MU FR variability (p=0.031). With progression from early to late elderly, both sexes showed decreased functional capacity at a similar rate. ConclusionFunctional deterioration occurs to a similar extent in both sexes from early to late elderly. However, throughout the majority of the elderly period males demonstrate a greater muscle size, strength, and functional performance. Older females have greater MUFR variability and worse force steadiness than older males. These findings help to address the lack of MU data in older females, and suggest earlier interventions are needed in older females to prevent functional deterioration and reduce the health-sex paradox within ageing humans.

physiology↗

bioRxiv2020

A physiological role for GABAA receptor desensitization - induction of long-term potentiation at inhibitory synapses

GABAA receptors (GABAARs) are pentameric ligand-gated ion channels distributed throughout the brain where they mediate synaptic and tonic inhibition. Following activation, these receptors undergo desensitization which involves entry into long-lived agonist-bound closed states. Although the kinetic effects of this state are recognised and its structural basis has been uncovered, the physiological impact of desensitization on inhibitory neurotransmission remains unknown. Here we describe an enduring new form of long-term potentiation at inhibitory synapses that elevates synaptic current amplitude for 24 hrs following desensitization of GABAARs in response to prolonged agonist exposure or allosteric modulation. Using receptor mutants and allosteric modulators we demonstrate that desensitization of GABAARs facilitates their phosphorylation by PKC, which increases the number of receptors at inhibitory synapses. These observations provide a new physiological relevance to the desensitized state of GABAARs, acting as a signal to regulate the efficacy of inhibitory synapses during prolonged periods of inhibitory neurotransmission.

neuroscience↗

bioRxiv2018

Heteromeric GABAA receptor structures in positively-modulated active states

Type-A {gamma}-aminobutyric acid (GABAA) receptors are pentameric ligand-gated ion channels (pLGICs), typically consisting of /{beta}/{gamma} subunit combinations. They are the principal mediators of inhibitory neurotransmission throughout the central nervous system and targets of major clinical drugs, such as benzodiazepines (BZDs) used to treat epilepsy, insomnia, anxiety, panic disorder and muscle spasm. However, the structures of heteromeric receptors and the molecular basis of BZD operation remain unknown. Here we report the cryo-EM structure of a human 1{beta}3{gamma}2 GABAAR in complex with GABA and a nanobody that acts as a novel positive allosteric modulator (PAM). The receptor subunits assume a unified quaternary activated conformation around an open pore. We also present crystal structures of engineered 5 and 5{gamma}2 GABAAR constructs, revealing the interfacial site for allosteric modulation by BZDs, including the binding modes and the conformational impact of the potent anxiolytic and partial PAM, bretazenil, and the BZD antagonist, flumazenil. These findings provide the foundation for understanding the mechanistic basis of GABAAR activation.

biophysics↗