Pharmacological and biochemical characterization of the beta-adrenergic signal transduction pathway in different segments of the respiratory tract.
Abstract: Although in the respiratory system there is great therapeutic interest in manipulating and understanding the beta-adrenoceptor-G-protein-adenylate cyclase (AC) signal transduction pathway, little is known on segmental differences among lung, bronchus, and trachea with regard to the receptor concentration and interaction to G-proteins and coupling to AC. In this study, patterns of distribution and absolute quantities of beta-adrenoceptor subtypes beta(1) and beta(2) were determined in membranes of equine lung parenchyma, bronchial and tracheal epithelium with the underlying smooth muscle by saturation and competition binding assays using the radioligand (-)-[125I]-iodocyanopindolol (ICYP). Additionally, the functional coupling of beta-adrenoceptors to G-proteins (assessed by beta-agonist competition binding in the presence and absence of GTP) as well as the coupling efficiency and biochemical activities of AC was investigated in each region. The specific ICYP binding was rapid, reversible, saturable with time and of high affinity. The radioligand binding identified more total beta-adrenoceptors in the lung than in bronchus or trachea (428+/-19, 162.4+/-4.8, 75.6+/-1.2 fmol/mg protein, respectively) with about 40% of receptors in the high affinity state. The beta(2)-adrenoceptor subtype predominated in all segments (approximately 74-80%), as the highly selective beta(2)-adrenoceptor antagonist ICI 118,551 was about 10,000 times more potent in inhibiting ICYP binding than was the beta(1)-selective adrenoceptor antagonist CGP 20712A, and beta-adrenoceptor agonists inhibited ICYP binding with an order of potency: (-)-isoprenaline>(-)-adrenaline>(-)-noradrenaline. The dissociation constant (K(d)) was higher in the trachea than in bronchus or lung (13.0+/-0.9 pM vs. 20.0+/-2.3 pM vs. 30.8+/-4.4 pM, P>>bronchus>lung), hence, the number of beta(2)-adrenoceptors correlated inversely with the amount of AC. We conclude that (1) the stoichiometry of components within the pulmonary beta-adrenoceptor-G-protein complex is segment-dependent, and (2) the receptor number or AC activity is possibly the rate-limiting factor in the beta-adrenoceptor-G-protein-AC-mediated physiological responses. Thus, it is speculated that this could have important therapeutic consequences in beta-adrenoceptor agonist-induced receptor regulation in bronchial asthma.
Publication Date: 2003-09-10 PubMed ID: 12963495DOI: 10.1016/s0006-2952(03)00460-xGoogle Scholar: Lookup
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- Journal Article
Summary
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The research investigates the beta-adrenoceptor (a type of protein) signal transduction pathway, a cellular communication process, in various parts of the respiratory tract such as the lung, bronchus, and trachea. Specifically, it measures receptor concentrations, their coupling with G-proteins and adenylate cyclase (AC), and how these factors vary between different sections of the respiratory pathway.
Methodology and Findings
- The research examines the presence and quantity of two beta-adrenoceptor subtypes, beta(1) and beta(2), in different segments of the equine respiratory system.
- The researchers used a radioactive compound called (-)-[125I]-iodocyanopindolol (ICYP) for saturation and competition assays to reveal the density and binding specificity of beta-adrenoceptors in each region.
- It was found that the lung had significantly more beta-adrenoceptors than the bronchus or trachea. Additionally, approximately 40% of these receptors were in a state of high affinity, effectively binding to the specified ligand.
- The beta(2)-adrenoceptor subtype was dominant in all respiratory segments, making up roughly 74–80% of the total. This was shown through competitive ligand-binding assays, further showing the ICYP radioligand’s binding dynamics.
- The connectivity constant (K(d)), which measures the strength of the receptor-ligand interaction, was higher in the trachea compared to the bronchus or lung, implying different receptor affinity across the segments.
Implications and Conclusions
- The AC activity and coupling of beta-adrenoceptors to G-proteins were shown to be dependent on the location within the respiratory pathway, being highest in the trachea.
- A correlation was revealed wherein the amount of AC activity seemed to inversely match the amount of beta(2)-adrenoceptors in a given segment.
- The research concluded that the stoichiometry, or proportion, of components within the beta-adrenoceptor-G-protein complex changes depending on the specific segment of the respiratory tract.
- The study also proposed that the receptor numbers or the activity level of AC could potentially be the limiting factors in the speed and effectiveness of cellular communication through the discussed pathway.
- Finally, the authors speculated that an improved understanding of these variations could have potential therapeutic implications in conditions like bronchial asthma, where the goal would be to enhance receptor activity using beta-adrenoceptor agonist drugs.
Cite This Article
APA
Abraham G, Kottke C, Dhein S, Ungemach FR.
(2003).
Pharmacological and biochemical characterization of the beta-adrenergic signal transduction pathway in different segments of the respiratory tract.
Biochem Pharmacol, 66(6), 1067-1081.
https://doi.org/10.1016/s0006-2952(03)00460-x Publication
Researcher Affiliations
- Faculty of Veterinary Medicine, Institute of Pharmacology, Pharmacy and Toxicology, Leipzig University, An den Tierkliniken 15, 04103 Leipzig, Germany. gabraham@rz.uni-leipzig.de
MeSH Terms
- Adenylyl Cyclases / metabolism
- Adrenergic beta-Agonists / pharmacology
- Adrenergic beta-Antagonists / pharmacology
- Animals
- Bronchi / metabolism
- Cyclic AMP / metabolism
- GTP-Binding Proteins / metabolism
- Horses
- Iodocyanopindolol / pharmacology
- Isoproterenol / pharmacology
- Lung / enzymology
- Lung / metabolism
- Radioligand Assay
- Receptors, Adrenergic, beta / metabolism
- Respiratory System
- Signal Transduction
- Trachea / metabolism
Citations
This article has been cited 11 times.- Alencar Filho EB, Ribeiro LAA, Carvalho TGC, Silva FS, Duarte-Filho LAMS, Barbosa EG, Menezes PMN, Tavares JF, da Silva MS, Silva BA. In vitro and in silico studies of 8(17),12E,14-labdatrien-18-oic acid in airways smooth muscle relaxation: new molecular insights about its mechanism of action.. Naunyn Schmiedebergs Arch Pharmacol 2021 May;394(5):885-902.
- Weiterer S, Kohlen T, Veit F, Sachs L, Uhle F, Lichtenstern C, Weigand MA, Henrich M. Galactomannan and Zymosan Block the Epinephrine-Induced Particle Transport in Tracheal Epithelium.. PLoS One 2015;10(11):e0143163.
- Hegde A, Strachan RT, Walker JK. Quantification of beta adrenergic receptor subtypes in beta-arrestin knockout mouse airways.. PLoS One 2015;10(2):e0116458.
- Ikeda T, Anisuzzaman AS, Yoshiki H, Sasaki M, Koshiji T, Uwada J, Nishimune A, Itoh H, Muramatsu I. Regional quantification of muscarinic acetylcholine receptors and β-adrenoceptors in human airways.. Br J Pharmacol 2012 Jul;166(6):1804-14.
- Poziomkowska-Gesicka I, Dzieciolowska-Baran E, Gawlikowska-Sroka A, Slowik-Zylka D, Sroczynski T. Evaluation of spirometry values in relation to beta-2-adrenergic receptor gene polymorphism.. Eur J Med Res 2010 Nov 4;15 Suppl 2(Suppl 2):135-40.
- Wang H, Li SY, Zhao CK, Zeng X. A system for screening agonists targeting beta2-adrenoceptor from Chinese medicinal herbs.. J Zhejiang Univ Sci B 2009 Apr;10(4):243-50.
- Shibeshi W, Abraham G, Kneuer C, Ellenberger C, Seeger J, Schoon HA, Ungemach FR. Isolation and culture of primary equine tracheal epithelial cells.. In Vitro Cell Dev Biol Anim 2008 Jul-Aug;44(7):179-84.
- Myslivecek J, Duysen EG, Lockridge O. Adaptation to excess acetylcholine by downregulation of adrenoceptors and muscarinic receptors in lungs of acetylcholinesterase knockout mice.. Naunyn Schmiedebergs Arch Pharmacol 2007 Oct;376(1-2):83-92.
- Abraham G, Kottke C, Ammer H, Dhein S, Ungemach FR. Segment-dependent expression of muscarinic acetylcholine receptors and G-protein coupling in the equine respiratory tract.. Vet Res Commun 2007 Feb;31(2):207-26.
- Kassahun WT, Günl B, Tannapfel A, Ungemach FR, Hauss J, Abraham G. Alpha1-and beta2-adrenoceptors in the human liver with mass-forming intrahepatic cholangiocarcinoma: density and coupling to adenylate cyclase and phospholipase C.. Naunyn Schmiedebergs Arch Pharmacol 2005 Nov;372(3):171-81.
- Vanneste G, Robberecht P, Lefebvre RA. Inhibitory pathways in the circular muscle of rat jejunum.. Br J Pharmacol 2004 Sep;143(1):107-18.
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