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The heterodimeric GABA B receptor, composed of GB1 and GB2 subunits, is a metabotropic G protein-coupled receptor (GPCR) activated by the neurotransmitter GABA. GABA binds to the extracellular domain of GB1 to activate G proteins through GB2. Here we show that GABA B receptors can be activated by mechanical forces, such as traction force and shear stress, in a GABA-independent manner. This GABA-independent mechano-activation of GABA B receptor is mediated by a direct interaction between integrins and the extracellular domain of GB1, indicating that GABA B receptor and integrin form a mechano-transduction complex. Mechanistically, shear stress promotes the binding of integrin to GB1 and induces an allosteric re-arrangement of GABA B receptor transmembrane domains towards an active conformation, culminating in receptor activation. Furthermore, we demonstrate that shear stress-induced GABA B receptor activation plays a crucial role in astrocyte remodeling. These findings reveal a role of GABA B receptor in mechano-transduction, uncovering a ligand-independent activation mechanism for GPCRs. In this study, the heterodimeric GABA B receptor, a class C G protein-coupled receptor for the neurotransmitter GABA, is found to be allosterically activated by mechanical forces in a GABA independent manner through a direct interaction with integrin.

The heterodimeric GABA receptor, composed of GB1 and GB2 subunits, is a metabotropic G protein-coupled receptor (GPCR) activated by the neurotransmitter GABA. GABA binds to the extracellular domain of GB1 to activate G proteins through GB2. Here we show that GABA receptors can be activated by mechanical forces, such as traction force and shear stress, in a GABA-independent manner. This GABA-independent mechano-activation of GABA receptor is mediated by a direct interaction between integrins and the extracellular domain of GB1, indicating that GABA receptor and integrin form a mechano-transduction complex. Mechanistically, shear stress promotes the binding of integrin to GB1 and induces an allosteric re-arrangement of GABA receptor transmembrane domains towards an active conformation, culminating in receptor activation. Furthermore, we demonstrate that shear stress-induced GABA receptor activation plays a crucial role in astrocyte remodeling. These findings reveal a role of GABA receptor in mechano-transduction, uncovering a ligand-independent activation mechanism for GPCRs.

The heterodimeric GABAB receptor, composed of GB1 and GB2 subunits, is a metabotropic G protein-coupled receptor (GPCR) activated by the neurotransmitter GABA. GABA binds to the extracellular domain of GB1 to activate G proteins through GB2. Here we show that GABAB receptors can be activated by mechanical forces, such as traction force and shear stress, in a GABA-independent manner. This GABA-independent mechano-activation of GABAB receptor is mediated by a direct interaction between integrins and the extracellular domain of GB1, indicating that GABAB receptor and integrin form a novel type of mechano-transduction complex. Mechanistically, shear stress promotes the binding of integrin to GB1 and induces an allosteric re-arrangement of GABAB receptor transmembrane domains towards an active conformation, culminating in receptor activation. Furthermore, we demonstrate that shear stress-induced GABAB receptor activation plays a crucial role in astrocyte remodeling. These findings reveal a previously unrecognized function of GABAB receptor in mechano-transduction, uncovering a novel ligand-independent activation mechanism for GPCRs.

Physical activity (PA) is a significant predictor of physical and mental health, particularly among older adults. In India and China, gendered social norms shape physical patterns, and the intensity of androcentric settings is different. As a result, the gendered perspective of physical activity and its association with health outcomes could be different in China and India. Therefore, the study examines gender differences in physical activity and their impact on health outcomes. This study utilizes nationally representative data from older adults aged 60 and above in India and China. Gender disaggregated physical activity is considered a key explanatory variable, and functional limitations (IADL/ADL), multimorbidity, and self-rated health are selected as outcome variables. Separate logistic regression analyses were conducted for males and females to examine the gender-specific associations between PA and health. Indian women show lower moderate PA (54.58%) than Chinese women (49.99%), with markedly fewer engaging in intense PA (12.35% vs. 24.01%). Health disparities are more severe in India: 56.15% report IADL limitations (China: 42.86%) and 25.2% ADL problems (China: 29.09%). While moderate PA strongly protects against poor SRH/ADL in both countries, Indian women face higher multimorbidity risks (aOR: 1.38 vs. China's Non-Significant) when inactive. This comparative study reveals that Indian women face greater physical activity disparities and worse functional health outcomes than Chinese women, highlighting the urgent need for gender-sensitive health interventions to address these inequities.

Background Physical activity (PA) is a significant predictor of physical and mental health, particularly among older adults. In India and China, gendered social norms shape physical patterns, and the intensity of androcentric settings is different. As a result, the gendered perspective of physical activity and its association with health outcomes could be different in China and India. Therefore, the study examines gender differences in physical activity and their impact on health outcomes. Methods This study utilizes nationally representative data from older adults aged 60 and above in India and China. Gender disaggregated physical activity is considered a key explanatory variable, and functional limitations (IADL/ADL), multimorbidity, and self-rated health are selected as outcome variables. Separate logistic regression analyses were conducted for males and females to examine the gender-specific associations between PA and health. Results Indian women show lower moderate PA (54.58%) than Chinese women (49.99%), with markedly fewer engaging in intense PA (12.35% vs. 24.01%). Health disparities are more severe in India: 56.15% report IADL limitations (China: 42.86%) and 25.2% ADL problems (China: 29.09%). While moderate PA strongly protects against poor SRH/ADL in both countries, Indian women face higher multimorbidity risks (aOR: 1.38 vs. China’s Non-Significant) when inactive. Conclusion This comparative study reveals that Indian women face greater physical activity disparities and worse functional health outcomes than Chinese women, highlighting the urgent need for gender-sensitive health interventions to address these inequities.

ObjectivesEosinophils possess pro-inflammatory functions in asthma. However, our recent studies have suggested that innate lymphoid cells type 2 (ILC2s) and eosinophils have proresolving properties in rheumatoid arthritis (RA). Nothing is known yet about the mechanisms determining the double-edged role of eosinophils. Therefore, we investigated whether asthma, a paradigm eosinophilic disease, can elicit resolution of chronic arthritis.MethodsOvalbumin-triggered eosinophilic asthma was combined with K/BxN serum-induced arthritis, where lung and synovial eosinophil subsets were compared by single-cell RNA sequencing (scRNA-seq). To investigate the involvement of the ILC2–interleukin-5 (IL-5) axis, hydrodynamic injection (HDI) of IL-25 and IL-33 plasmids, IL-5 reporter mice and anti-IL-5 antibody treatment were used. In patients with RA, the presence of distinct eosinophil subsets was examined in peripheral blood and synovial tissue. Disease activity of patients with RA with concomitant asthma was monitored before and after mepolizumab (anti-IL-5 antibody) therapy.ResultsThe induction of eosinophilic asthma caused resolution of murine arthritis and joint tissue protection. ScRNA-seq revealed a specific subset of regulatory eosinophils (rEos) in the joints, distinct from inflammatory eosinophils in the lungs. Mechanistically, synovial rEos expanded on systemic upregulation of IL-5 released by lung ILC2s. Eosinophil depletion abolished the beneficial effect of asthma on arthritis. rEos were consistently present in the synovium of patients with RA in remission, but not in active stage. Remarkably, in patients with RA with concomitant asthma, mepolizumab treatment induced relapse of arthritis.ConclusionThese findings point to a hitherto undiscovered proresolving signature in an eosinophil subset that stimulates arthritis resolution.