Publications by authors named "Nikhil Karmacharya"

Leucine-rich repeat containing 8A (LRRC8A) is an obligatory constituent of the volume-regulated anion channel (VRAC) that is fundamental to a wide range of biological processes, including regulating cell size, proliferation, and migration. Here we explored the physiological role for VRAC in excitation-contraction (E-C) coupling and shortening of human airway smooth muscle (HASM). In HASM cells, pharmacological inhibition of VRAC with DCPIB (0.

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Bronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of β adrenergic receptor (βAR) agonists and muscarinic antagonists shows superior bronchoprotective effects compared to these agents individually. Navafenterol (AZD8871) is a single-molecule, dual pharmacology agent combining muscarinic antagonist and βAR agonist functions, currently in development as a COPD therapeutic.

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Bronchomotor tone modulated by airway smooth muscle shortening represents a key mechanism that increases airway resistance in asthma. Altered glucose metabolism in inflammatory and airway structural cells is associated with asthma. Although these observations suggest a causal link between glucose metabolism and airway hyperresponsiveness, the mechanisms are unclear.

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Obesity can aggravate asthma by enhancing airway hyperresponsiveness (AHR) and attenuating response to treatment. However, the precise mechanisms linking obesity and asthma remain unknown. Human airway smooth muscle (HASM) cells exhibit amplified excitation-contraction (EC) coupling and force generation in obesity.

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In most living cells, the second-messenger roles for adenosine 3',5'-cyclic monophosphate (cAMP) are short-lived, confined to the intracellular space, and tightly controlled by the binary switch-like actions of Gα (stimulatory G protein)-activated adenylyl cyclase (cAMP production) and cAMP-specific PDE (cAMP breakdown). Here, by using human airway smooth muscle (HASM) cells in culture as a model, we report that activation of the cell-surface βAR (β-adrenoceptor), a G-coupled GPCR (G protein-coupled receptor), evokes cAMP egress to the extracellular space. Increased extracellular cAMP levels ([cAMP]) are long-lived in culture and are induced by receptor-dependent and receptor-independent mechanisms in such a way as to define a universal response class of increased intracellular cAMP levels ([cAMP]).

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Article Synopsis
  • The study investigates the role of free fatty acid receptors (FFAR1 and FFAR4) in human airway smooth muscle (HASM) cells, particularly how these receptors contribute to cell proliferation and contraction in the context of obesity-related disorders.
  • Using various methods, researchers treated HASM cells with FFAR1 agonists and measured changes in calcium mobilization, myosin light chain (MLC) phosphorylation, and tension development, ultimately finding that the FFAR1 agonist TAK875 decreased MLC phosphorylation and muscle tension despite unchanged calcium levels.
  • Results indicate that this inhibitory effect of TAK875 on MLC phosphorylation persisted even in cells desensitized to β-adrenergic agonists, suggesting a complex interplay of
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Article Synopsis
  • Recent research has found sensory G protein-coupled receptors in the smooth muscle of human bronchi, indicating potential new targets for therapies in obstructive lung diseases.
  • This study reveals that various volatile odorants can influence the contractility of airway smooth muscle cells, where some substances paradoxically cause both calcium increases and muscle relaxation.
  • The findings suggest that the mechanism behind the receptor's action involves store-operated calcium entry and specific chloride channels, highlighting a novel signaling pathway that could lead to new treatments.
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Background: Asthma exacerbations evoke emergency room visits, progressive loss of lung function and increased mortality. Environmental and industrial toxicants exacerbate asthma, although the underlying mechanisms are unknown. We assessed whether 3 distinct toxicants, salicylic acid (SA), toluene diisocyanate (TDI), and 1-chloro-2,4-dinitrobenzene (DNCB) induced airway hyperresponsiveness (AHR) through modulating excitation-contraction coupling in human airway smooth muscle (HASM) cells.

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