The Role of Regulator of G-Protein-Signaling 4 (RGS4) in Control of Airway Hyper-responsiveness in Asthma

Abstract

Abstract Asthma is a common respiratory disease characterized by airway hyper-responsiveness (AHR), inflammation, and airway obstruction. In most patients, this disease can be managed with steroids and bronchodilators. However, these treatments are not effective for the 15%-25% of patients with severe asthma who may develop fixed airway obstruction due to increased airway smooth muscle (ASM) mass. ASM cells control airway patency through G-protein coupled receptors (GPCRs). Namely, GPCRs can activate the IP3 pathway to induce calcium release and airway contraction. Regulators of G-protein signaling (RGS) are a family of proteins that are known to negatively regulate the activity of GPCRs. In ASM cells, RGS4 is relatively abundant compared to other RGS4 proteins. In people with asthma, increased RGS4 expression is observed in the group with greatest impairment in lung function. We hypothesize that aberrant RGS4 expression and/or function contributes to AHR through dysregulated GPCR signaling in ASM cells. We studied bacterial artificial chromosome (BAC) transgenic (Tg) mice, which overexpress both RGS4 and eGFP under the control of endogenous RGS4 promoter. In models of acute asthma, Tg mice exhibited reduced AHR as assessed by measurements of lung resistance in live, anesthetized mice and contraction of precision cut lung slices. These findings suggest that RGS4 is an important controller of bronchial tone in asthma through its effects on contraction signaling in ASM cells.