Regulator of G protein signaling 2 is a key modulator of airway hyperresponsiveness.
BACKGROUND
Drugs targeting individual G protein-coupled receptors are used as asthma therapies, but this strategy is limited because of G protein-coupled receptor signal redundancy. Regulator of G protein signaling 2 (RGS2), an intracellular selective inhibitor of multiple bronchoconstrictor receptors, may play a central role in the pathophysiology and treatment of asthma.


OBJECTIVE
We defined functions and mechanisms of RGS2 in regulating airway hyperresponsiveness (AHR), the pathophysiologic hallmark of asthma.


METHODS
Real-time PCR and Western blot were used to determine changes in RGS2 expression in ovalbumin-sensitized/-challenged mice. We also used immunohistochemistry and real-time PCR to compare RGS2 expression between human asthmatic and control subjects. The AHR of RGS2 knockout mice was assessed by using invasive tracheostomy and unrestrained plethysmography. Effects of loss of RGS2 on mouse airway smooth muscle (ASM) remodeling, contraction, intracellular Ca(2+), and mitogenic signaling were determined in vivo and in vitro.


RESULTS
RGS2 was highly expressed in human and murine bronchial epithelium and ASM and was markedly downregulated in lungs of ovalbumin-sensitized/-challenged mice. Lung tissues and blood monocytes from asthma patients expressed significantly lower RGS2 protein (lung) and mRNA (monocytes) than from nonasthma subjects. The extent of reduction of RGS2 on human monocytes correlated with increased AHR. RGS2 knockout caused spontaneous AHR in mice. Loss of RGS2 augmented Ca(2+) mobilization and contraction of ASM cells. Loss of RGS2 also increased ASM mass and stimulated ASM cell growth via extracellular signal-regulated kinase and phosphatidylinositol 3-kinase pathways.


CONCLUSIONS
We identified RGS2 as a potent modulator of AHR and a potential novel therapeutic target for asthma.
Department of Pharmacology, Creighton University School of Medicine, Omaha, NE 68178, USA.
Yan
Y
Xie
Haihong
H
Jiang
Hoai
H
Nguyen
Shuping
S
Jia
Abdo
A
Berro
Reynold A
RA
Panettieri
Dennis W
DW
Wolff
Peter W
PW
Abel
Thomas B
TB
Casale
Yaping
Y
Tu
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000209:etiology*; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D020710:RGS Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D015398:Signal Transduction
D020710:RGS Proteins; C087182:RGS2 protein, human; C105345:Rgs2 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium