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Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function.

Publication ,  Journal Article
Pera, T; Hegde, A; Deshpande, DA; Morgan, SJ; Tiegs, BC; Theriot, BS; Choi, YH; Walker, JKL; Penn, RB
Published in: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
October 2015

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.

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Published In

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

DOI

EISSN

1530-6860

ISSN

0892-6638

Publication Date

October 2015

Volume

29

Issue

10

Start / End Page

4227 / 4235

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • beta-Arrestin 1
  • Signal Transduction
  • Respiratory System
  • Receptors, Muscarinic
  • Receptors, G-Protein-Coupled
  • Receptors, Adrenergic, beta
  • RNA Interference
  • Muscle, Smooth
 

Citation

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Pera, T., Hegde, A., Deshpande, D. A., Morgan, S. J., Tiegs, B. C., Theriot, B. S., … Penn, R. B. (2015). Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 29(10), 4227–4235. https://doi.org/10.1096/fj.15-273094
Pera, Tonio, Akhil Hegde, Deepak A. Deshpande, Sarah J. Morgan, Brian C. Tiegs, Barbara S. Theriot, Yeon H. Choi, Julia K. L. Walker, and Raymond B. Penn. “Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function.FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology 29, no. 10 (October 2015): 4227–35. https://doi.org/10.1096/fj.15-273094.
Pera T, Hegde A, Deshpande DA, Morgan SJ, Tiegs BC, Theriot BS, et al. Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2015 Oct;29(10):4227–35.
Pera, Tonio, et al. “Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function.FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 29, no. 10, Oct. 2015, pp. 4227–35. Epmc, doi:10.1096/fj.15-273094.
Pera T, Hegde A, Deshpande DA, Morgan SJ, Tiegs BC, Theriot BS, Choi YH, Walker JKL, Penn RB. Specificity of arrestin subtypes in regulating airway smooth muscle G protein-coupled receptor signaling and function. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2015 Oct;29(10):4227–4235.

Published In

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

DOI

EISSN

1530-6860

ISSN

0892-6638

Publication Date

October 2015

Volume

29

Issue

10

Start / End Page

4227 / 4235

Related Subject Headings

  • beta-Arrestins
  • beta-Arrestin 2
  • beta-Arrestin 1
  • Signal Transduction
  • Respiratory System
  • Receptors, Muscarinic
  • Receptors, G-Protein-Coupled
  • Receptors, Adrenergic, beta
  • RNA Interference
  • Muscle, Smooth