Thursday, November 21, 2024
11/21/2024
Summary The beta-2-adrenoceptor (2AR) is the most studied and best understood member of the G protein-coupled receptor superfamily. And for good reason: it plays an important role in the regulating the function of numerous cells types, and is the therapeutic target in the management of various diseases, including asthma. Indeed, the last several decades have produced intensive research into how the 2AR is activated, and how it is regulated, resulting in the development of new drugs, the majority being 2AR agonists with improved efficacy, duration of action, and safety. Underlying these efforts have been basic science discoveries into how 2ARs are regulated, with much of the research focused on discovering modes of receptor desensitization mediated by post- translational modifications of the receptor. During the 25 years of HL05806, we have focused on establishing mechanisms by which the 2AR is regulated in airway cells and in the context of lung and asthma biology, to significantly advance our understanding of asthma pathobiology and the needs of asthma drug development. In this cycle of HL058506, we will explore a fascinating new mode of GPCR regulation recently discovered to apply to 3 adrenoceptor (3AR) signaling and function in adipocytes by our co-I Tim McKinsey. In Bagchi et al. (PNAS 2022), the McKinsey lab discovered that HDAC11 functions to de-myristoylate lysine residues on the A kinase anchoring protein (AKAP) gravin, which localizes the 3AR to plasma membrane lipid rafts, enabling effective coupling with transmembrane signaling partners important for signaling and protective thermogenic gene expression. New data generated herein by the Penn and McKinsey labs suggest a similar regulation of the 2AR in airway smooth muscle (ASM) exists, prompting us to pursue a comprehensive mechanistic analysis of this novel mode of GPCR regulation by testing the hypothesis that inhibitory targeting of HDAC11 demyristoylation of gravin augments 2AR, and possibly EP receptor, signaling in ASM by preferentially distributing receptors to plasma membrane signaling-competent domains, resulting in increased capacity of these receptors to regulate ASM functions. The proposal is heavily weighted in basic science biological/biochemical/imaging approaches to understand the mechanisms underlying HDAC11 regulation of ASM GPCRs, recognizing the importance of this foundation for understanding the ultimate physiological and clinical significance of this phenomenon. In Aim 1 we will establish mechanisms of HDAC11 regulation of gravin in HASM using molecular, genetic, and pharmacological strategies in ASM cultures. In Aim 2 we will employ both heterologous expression systems as well as primary HASM cells to establish how HDAC11 regulation of gravin regulates Gs-coupled GPCRs in ASM through regulation of receptor localization, signaling, desensitization, and resensitization. In Aim 3 we will establish how HDAC11/gravin -dependent regulation of GPCR signaling translates into altered GPCR function in ASM and the lung, and the effect of the inhibiting HDAC11, using pharmacological and genetic means, on the in vivo asthma phenotype.
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