Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Respiratory Research
Published in: Respiratory Research 1/2010

Open Access 01-12-2010 | Research

Smoking-mediated up-regulation of GAD67 expression in the human airway epithelium

Authors: Guoqing Wang, Rui Wang, Barbara Ferris, Jacqueline Salit, Yael Strulovici-Barel, Neil R Hackett, Ronald G Crystal

Published in: Respiratory Research | Issue 1/2010

Login to get access

Abstract

Background

The production of gamma-amino butyric acid (GABA) is dependent on glutamate decarboxylases (GAD65 and GAD67), the enzymes that catalyze the decarboxylation of glutamate to GABA. Based on studies suggesting a role of the airway epithelial GABAergic system in asthma-related mucus overproduction, we hypothesized that cigarette smoking, another disorder associated with increased mucus production, may modulate GABAergic system-related gene expression levels in the airway epithelium.

Methods

We assessed expression of the GABAergic system in human airway epithelium obtained using bronchoscopy to sample the epithelium and microarrays to evaluate gene expression. RT-PCR was used to confirm gene expression of GABAergic system gene in large and small airway epithelium from heathy nonsmokers and healthy smokers. The differences in the GABAergic system gene was further confirmed by TaqMan, immunohistochemistry and Western analysis.

Results

The data demonstrate there is a complete GABAergic system expressed in the large and small human airway epithelium, including glutamate decarboxylase, GABA receptors, transporters and catabolism enzymes. Interestingly, of the entire GABAergic system, smoking modified only the expression of GAD67, with marked up-regulation of GAD67 gene expression in both large (4.1-fold increase, p < 0.01) and small airway epithelium of healthy smokers (6.3-fold increase, p < 0.01). At the protein level, Western analysis confirmed the increased expression of GAD67 in airway epithelium of healthy smokers compared to healthy nonsmokers (p < 0.05). There was a significant positive correlation between GAD67 and MUC5AC gene expression in both large and small airway epithelium (p < 0.01), implying a link between GAD67 and mucin overproduction in association with smoking.

Conclusions

In the context that GAD67 is the rate limiting enzyme in GABA synthesis, the correlation of GAD67 gene expression with MUC5AC expressions suggests that the up-regulation of airway epithelium expression of GAD67 may contribute to the increase in mucus production observed in association with cigarette smoking.

Trial registration

NCT00224198; NCT00224185
Appendix
Available only for authorised users
Literature
1.
Tillakaratne NJ, Medina-Kauwe L, Gibson KM: Gamma-aminobutyric acid (GABA) metabolism in mammalian neural and nonneural tissues. Comp Biochem Physiol A Physiol 1995, 112:247–263.CrossRefPubMed
2.
Owens DF, Kriegstein AR: Is there more to GABA than synaptic inhibition? Nat Rev Neurosci 2002, 3:715–727.CrossRefPubMed
3.
Watanabe M, Maemura K, Kanbara K, Tamayama T, Hayasaki H: GABA and GABA receptors in the central nervous system and other organs. Int Rev Cytol 2002, 213:1–47.CrossRefPubMed
4.
5.
Dicpinigaitis PV, Spungen AM, Bauman WA, Absgarten A, Almenoff PL: Inhibition of bronchial hyperresponsiveness by the GABA-agonist baclofen. Chest 1994, 106:758–761.CrossRefPubMed
6.
7.
Xiang YY, Wang S, Liu M, Hirota JA, Li J, Ju W, Fan Y, Kelly MM, Ye B, Orser B, O'Byrne PM, Inman MD, Yang X, Lu WY: A GABAergic system in airway epithelium is essential for mucus overproduction in asthma. Nat Med 2007, 13:862–867.CrossRefPubMed
8.
Mizuta K, Xu D, Pan Y, Comas G, Sonett JR, Zhang Y, Panettieri RA Jr, Yang J, Emala CW Sr: GABAA receptors are expressed and facilitate relaxation in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2008, 294:L1206-L1216.CrossRefPubMedPubMedCentral
9.
Gleason NR, Gallos G, Zhang Y, Emala CW: The GABAA agonist muscimol attenuates induced airway constriction in guinea pigs in vivo. J Appl Physiol 2009, 106:1257–1263.CrossRefPubMedPubMedCentral
10.
Maestrelli P, Saetta M, Mapp CE, Fabbri LM: Remodeling in response to infection and injury. Airway inflammation and hypersecretion of mucus in smoking subjects with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001, 164:S76-S80.CrossRefPubMed
11.
Voynow JA, Gendler SJ, Rose MC: Regulation of mucin genes in chronic inflammatory airway diseases. Am J Respir Cell Mol Biol 2006, 34:661–665.CrossRefPubMed
12.
13.
Carolan BJ, Harvey BG, De BP, Vanni H, Crystal RG: Decreased expression of intelectin 1 in the human airway epithelium of smokers compared to nonsmokers. J Immunol 2008, 181:5760–5767.CrossRefPubMedPubMedCentral
14.
Hackett NR, Heguy A, Harvey BG, O'Connor TP, Luettich K, Flieder DB, Kaplan R, Crystal RG: Variability of antioxidant-related gene expression in the airway epithelium of cigarette smokers. Am J Respir Cell Mol Biol 2003, 29:331–343.CrossRefPubMed
15.
Harvey BG, Heguy A, Leopold PL, Carolan BJ, Ferris B, Crystal RG: Modification of gene expression of the small airway epithelium in response to cigarette smoking. J Mol Med 2007, 85:39–53.CrossRefPubMed
16.
17.
Tohda Y, Ohkawa K, Kubo H, Muraki M, Fukuoka M, Nakajima S: Role of GABA receptors in the bronchial response: studies in sensitized guinea-pigs. Clin Exp Allergy 1998, 28:772–777.CrossRefPubMed
18.
Attwell D, Barbour B, Szatkowski M: Nonvesicular release of neurotransmitter. Neuron 1993, 11:401–407.CrossRefPubMed
19.
Schousboe A, Waagepetersen HS: GABA: homeostatic and pharmacological aspects. Prog Brain Res 2007, 160:9–19.CrossRefPubMed
20.
Gadea A, Lopez-Colome AM: Glial transporters for glutamate, glycine, and GABA: II. GABA transporters. J Neurosci Res 2001, 63:461–468.CrossRefPubMed
21.
Osawa Y, Xu D, Sternberg D, Sonett JR, D'Armiento J, Panettieri RA, Emala CW: Functional expression of the GABAB receptor in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 2006, 291:L923-L931.CrossRefPubMed
22.
Mizuta K, Osawa Y, Mizuta F, Xu D, Emala CW: Functional expression of GABAB receptors in airway epithelium. Am J Respir Cell Mol Biol 2008, 39:296–304.CrossRefPubMedPubMedCentral
23.
Yabumoto Y, Watanabe M, Ito Y, Maemura K, Otsuki Y, Nakamura Y, Yanagawa Y, Obata K, Watanabe K: Expression of GABAergic system in pulmonary neuroendocrine cells and airway epithelial cells in GAD67-GFP knock-in mice. Med Mol Morphol 2008, 41:20–27.CrossRefPubMed
24.
Jin N, Guo Y, Sun P, Bell A, Chintagari NR, Bhaskaran M, Rains K, Baviskar P, Chen Z, Weng Tm, Liu L: Ionotropic GABA receptor expression in the lung during development. Gene Expr Patterns 2008, 8:397–403.CrossRefPubMedPubMedCentral
25.
Jin N, Narasaraju T, Kolliputi N, Chen J, Liu L: Differential expression of GABAA receptor pi subunit in cultured rat alveolar epithelial cells. Cell Tissue Res 2005, 321:173–183.CrossRefPubMed
26.
Gallos G, Zaidi S, Yim P, Zhang Y, Virag L, Whittington R, Emala C: Airway Epithelium Is The Predominant Cellular Source Of Endogenous Airway GABA. Am J Respir Crit Care Med 2010, 181:A6455.
27.
Zaidi S, Gallos G, Yim P, Emala C: Regulation Of Functional GABA Transporter 2 In Human Airway Smooth Muscle And Epithelial Cells. Am J Respir Crit Care Med 2010, 181:A6432.
28.
Lamigeon C, Bellier JP, Sacchettoni S, Rujano M, Jacquemont B: Enhanced neuronal protection from oxidative stress by coculture with glutamic acid decarboxylase-expressing astrocytes. J Neurochem 2001, 77:598–606.CrossRefPubMed
29.
Lamigeon C, Prod'Hon C, De FV, Michoudet C, Jacquemont B: Enhancement of neuronal protection from oxidative stress by glutamic acid decarboxylase delivery with a defective herpes simplex virus vector. Exp Neurol 2003, 184:381–392.CrossRefPubMed
30.
Tamaoki J: Ion channel regulation. In Antibodies as anti-inflammatory and immunomodulatory agents. Edited by: Rubin BK, Tamaoki J. Switzerland: Bikhäuser Verlag Basel; 2005:133–144.CrossRef
31.
Tarran R, Button B, Picher M, Paradiso AM, Ribeiro CM, Lazarowski ER, Zhang L, Collins PL, Pickles RJ, Fredberg JJ, Boucher RC: Normal and cystic fibrosis airway surface liquid homeostasis. The effects of phasic shear stress and viral infections. J Biol Chem 2005, 280:35751–35759.CrossRefPubMedPubMedCentral
32.
Satta R, Maloku E, Zhubi A, Pibiri F, Hajos M, Costa E, Guidotti A: Nicotine decreases DNA methyltransferase 1 expression and glutamic acid decarboxylase 67 promoter methylation in GABAergic interneurons. Proc Natl Acad Sci USA 2008, 105:16356–16361.CrossRefPubMedPubMedCentral
33.
Dong E, Guidotti A, Grayson DR, Costa E: Histone hyperacetylation induces demethylation of reelin and 67-kDa glutamic acid decarboxylase promoters. Proc Natl Acad Sci USA 2007, 104:4676–4681.CrossRefPubMedPubMedCentral
34.
Kundakovic M, Chen Y, Costa E, Grayson DR: DNA methyltransferase inhibitors coordinately induce expression of the human reelin and glutamic acid decarboxylase 67 genes. Mol Pharmacol 2007, 71:644–653.CrossRefPubMed
35.
Al-Wadei HA, Plummer HK III, Schuller HM: Nicotine stimulates pancreatic cancer xenografts by systemic increase in stress neurotransmitters and suppression of the inhibitory neurotransmitter gamma-aminobutyric acid. Carcinogenesis 2009, 30:506–511.CrossRefPubMedPubMedCentral
36.
Choi SE, Noh HL, Kim HM, Yoon JW, Kang Y: Streptozotocin upregulates GAD67 expression in MIN6N8a mouse beta cells. J Autoimmun 2002, 19:1–8.CrossRefPubMed
37.
Luo Y, Lathia J, Mughal M, Mattson MP: SDF1alpha/CXCR4 signaling, via ERKs and the transcription factor Egr1, induces expression of a 67-kDa form of glutamic acid decarboxylase in embryonic hippocampal neurons. J Biol Chem 2008, 283:24789–24800.CrossRefPubMedPubMedCentral
38.
Kim KS, Kang Y, Choi SE, Kim JH, Kim HM, Sun B, Jun HS, Yoon JW: Modulation of glucocorticoid-induced GAD expression in pancreatic beta-cells by transcriptional activation of the GAD67 promoter and its possible effect on the development of diabetes. Diabetes 2002, 51:2764–2772.CrossRefPubMed
39.
Wei J, Wu JY: Post-translational regulation of L-glutamic acid decarboxylase in the brain. Neurochem Res 2008, 33:1459–1465.CrossRefPubMed
40.
Hirota JA, Budelsky A, Smith D, Lipsky B, Ellis R, Xiang YY, Lu WY, Inman MD: The role of interleukin-4Ralpha in the induction of glutamic acid decarboxylase in airway epithelium following acute house dust mite exposure. Clin Exp Allergy 2010, 40:820–830.CrossRefPubMed
41.
Fu XW, Wood K, Spindel ER: Prenatal Nicotine Exposure Increases GABA Signaling and Mucin Expression in Airway Epithelium. Am J Respir Cell Mol Biol 2010.
42.
Miwa JM, Stevens TR, King SL, Caldarone BJ, Ibanez-Tallon I, Xiao C, Fitzsimonds RM, Pavlides C, Lester HA, Picciotto MR, Heintz N: The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo. Neuron 2006, 51:587–600.CrossRefPubMed
43.
Fu X, Miwa J, Spindel E: Lynx1 Modulates Communication Between Nicotinic And GABAergic Signaling In Airway Epithelium: A New Way To Target Smoking-induced Lung Disease. Am J Respir Crit Care Med 2010, 181:A4149.
44.
Gundavarapu S, Wilder JA, Rir-Sim-Ah J, Mishra N, Singh SP, Jaramillo R, Harrod KS, Tesfaigzi Y, Sopori ML: Modulation Of Mucus Cell Metaplasia By Cigarette Smoke/Nicotine Through GABAA Receptor Expression. Am J Respir Crit Care Med 2010, 181:A5442.
45.
Metadata
Title
Smoking-mediated up-regulation of GAD67 expression in the human airway epithelium
Authors
Guoqing Wang
Rui Wang
Barbara Ferris
Jacqueline Salit
Yael Strulovici-Barel
Neil R Hackett
Ronald G Crystal
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2010
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/1465-9921-11-150

Other articles of this Issue 1/2010

Respiratory Research 1/2010 Go to the issue

Research

DMF inhibits PDGF-BB induced airway smooth muscle cell proliferation through induction of heme-oxygenase-1

Research

Hypertonic saline increases lung epithelial lining fluid glutathione and thiocyanate: two protective CFTR-dependent thiols against oxidative injury

Research

Dimethylthiourea protects against chlorine induced changes in airway function in a murine model of irritant induced asthma

Research

JNK activation is responsible for mucus overproduction in smoke inhalation injury

Research

Nebulization of the acidified sodium nitrite formulation attenuates acute hypoxic pulmonary vasoconstriction

Research

NO2 inhalation induces maturation of pulmonary CD11c+ cells that promote antigen-specific CD4+ T cell polarization
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine
Image Credits