Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function.
Journal Article
Arrestins have been shown to regulate numerous G protein-coupled receptors (GPCRs) in studies employing receptor/arrestin overexpression in artificial cell systems. Which arrestin isoforms regulate which GPCRs in primary cell types is poorly understood. We sought to determine the effect of β-arrestin-1 or β-arrestin-2 inhibition or gene ablation on signaling and function of multiple GPCRs endogenously expressed in airway smooth muscle (ASM). In vitro [second messenger (calcium, cAMP generation)], ex vivo (ASM tension generation in suspended airway), and in vivo (invasive airway resistance) analyses were performed on human ASM cells and murine airways/whole animal subject to β-arrestin-1 or -2 knockdown or knockout (KO). In both human and murine model systems, knockdown or KO of β-arrestin-2 relative to control missense small interfering RNA or wild-type mice selectively increased (40-60%) β2-adrenoceptor signaling and function. β-arrestin-1 knockdown or KO had no effect on signaling and function of β2-adrenoceptor or numerous procontractile GPCRs, but selectively inhibited M3 muscarinic acetylcholine receptor signaling (∼50%) and function (∼25% ex vivo, >50% in vivo) without affecting EC50 values. Arrestin subtypes differentially regulate ASM GPCRs and β-arrestin-1 inhibition represents a novel approach to managing bronchospasm in obstructive lung diseases.
Full Text
Duke Authors
Cited Authors
- Pera, T; Hegde, A; Deshpande, DA; Morgan, SJ; Tiegs, BC; Theriot, BS; Choi, YH; Walker, JKL; Penn, RB
Published Date
- October 2015
Published In
Volume / Issue
- 29 / 10
Start / End Page
- 4227 - 4235
PubMed ID
- 26103985
Pubmed Central ID
- 26103985
Electronic International Standard Serial Number (EISSN)
- 1530-6860
International Standard Serial Number (ISSN)
- 0892-6638
Digital Object Identifier (DOI)
- 10.1096/fj.15-273094
Language
- eng