and specific aims): Beta-adrenergic receptors (b2ARs) on airway smooth muscle play an important role in regulating airway smooth muscle tone and airway patency, while beta-sympathomimetic drugs are the most widely used agents in asthma therapy and are universally recognized as the treatment of choice for acute asthma attacks. Despite the clinical importance of beta-agonists and a good understanding of how b2AR activation promotes airway smooth muscle relaxation, surprisingly little is known regarding the manner in which the b2AR signaling pathway is regulated in airway smooth muscle. The long-term objective of this project is to delineate the molecular and cellular mechanisms by which relevant physiological agents, such as inflammatory mediators, glucocorticoids, and beta-agonists themselves, alter b2AR responsiveness in human airway smooth muscle (HASM).
The specific aims are: 1) characterization of the desensitization and recovery from desensitization of b2AR function in HASM cells; 2) characterization of the principal mechanisms by which b2AR signaling is regulated during the desensitization and resensitization processes; and 3) identification of the role of protein kinases in these processes.
|Singh, Jagmohan; Mohanty, Ipsita; Addya, Sankar et al. (2017) Role of differentially expressed microRNA-139-5p in the regulation of phenotypic internal anal sphincter smooth muscle tone. Sci Rep 7:1477|
|Billington, Charlotte K; Penn, Raymond B; Hall, Ian P (2017) ?2 Agonists. Handb Exp Pharmacol 237:23-40|
|Chan, Tung O; Zhang, Jin; Tiegs, Brian C et al. (2015) Akt kinase C-terminal modifications control activation loop dephosphorylation and enhance insulin response. Biochem J 471:37-51|
|Penn, Raymond B; Bond, Richard A; Walker, Julia K L (2014) GPCRs and arrestins in airways: implications for asthma. Handb Exp Pharmacol 219:387-403|
|Pera, Tonio; Penn, Raymond B (2014) Crosstalk between beta-2-adrenoceptor and muscarinic acetylcholine receptors in the airway. Curr Opin Pharmacol 16:72-81|
|Deshpande, Deepak A; Yan, Huandong; Kong, Kok-Choi et al. (2014) Exploiting functional domains of GRK2/3 to alter the competitive balance of pro- and anticontractile signaling in airway smooth muscle. FASEB J 28:956-65|
|Morgan, Sarah J; Deshpande, Deepak A; Tiegs, Brian C et al. (2014) ?-Agonist-mediated relaxation of airway smooth muscle is protein kinase A-dependent. J Biol Chem 289:23065-74|
|Billington, Charlotte K; Ojo, Oluwaseun O; Penn, Raymond B et al. (2013) cAMP regulation of airway smooth muscle function. Pulm Pharmacol Ther 26:112-20|
|Horvat, Sarah J; Deshpande, Deepak A; Yan, Huandong et al. (2012) A-kinase anchoring proteins regulate compartmentalized cAMP signaling in airway smooth muscle. FASEB J 26:3670-9|
|Codina, Juan; Opyd, Timothy S; Powell, Zachary B et al. (2011) pH-dependent regulation of the ýý-subunit of H+-K+-ATPase (HKýý2). Am J Physiol Renal Physiol 301:F536-43|
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