QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heubach, J. F. Articles by Kaumann, A. J. Search for Related Content PubMed PubMed Citation Articles by Heubach, J. F. Articles by Kaumann, A. J.

Epinephrine Activates Both G_s and G_i Pathways, but Norepinephrine Activates Only the G_s Pathway through Human ₂-Adrenoceptors Overexpressed in Mouse Heart

Institute of Pharmacology and Toxicology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany (J.F.H., U.R.); and Department of Physiology, University of Cambridge, Cambridge, United Kingdom (A.J.K.)

Isoproterenol increases and decreases contractile force at low and high concentrations, respectively, through ₂-adrenoceptors overexpressed in transgenic mouse heart (TG4), consistent with activation of both G_s and G_i proteins. Using TG4 hearts, we demonstrated that epinephrine behaves like isoproterenol, but norepinephrine does not. Epinephrine both increased (-log EC₅₀M = 9.4) and decreased (-log EC₅₀M = 6.5) left atrial force. Pertussis toxin (PTX) abolished the negative inotropic effects of epinephrine, consistent with mediation through G_i protein. Norepinephrine only increased contractile force (-log EC₅₀M = 7.5). Norepinephrine (10-100 µM) prevented the positive inotropic effects but hardly affected the negative inotropic effects of epinephrine. Cardiodepressive epinephrine concentrations (1-10 µM) antagonized the positive inotropic effects of norepinephrine. In the free wall of TG4 right ventricle, norepinephrine and low epinephrine concentrations caused positive inotropic effects, and high epinephrine concentrations caused PTX-sensitive negative inotropic effects, as observed in the left atrium. Epinephrine (10 nM), a concentration causing maximum increase in contractile force, and norepinephrine (1 and 100 µM) increased cAMP-dependent protein kinase activity in TG4 left ventricle. Cardiodepressive concentrations of epinephrine (1 and 100 µM) did not increase cAMP-dependent protein kinase activity. The inotropic results were simulated with a model of two ₂-adrenoceptor sites. For one site involved in receptor coupling to G_s, both epinephrine and norepinephrine compete. The other site, recognized by epinephrine but not by norepinephrine, leads to receptor G_i coupling.

Address correspondence to: Dr. Alberto J. Kaumann, Department of Physiology, University of Cambridge, Downing Street, Cambridge CB2 3EG, United Kingdom. E-mail: ajk41{at}hermes.cam.ac.uk

This article has been cited by other articles:

				Y. Wang, V. De Arcangelis, X. Gao, B. Ramani, Y.-s. Jung, and Y. Xiang Norepinephrine- and Epinephrine-induced Distinct 2-Adrenoceptor Signaling Is Dictated by GRK2 Phosphorylation in Cardiomyocytes J. Biol. Chem., January 25, 2008; 283(4): 1799 - 1807. [Abstract] [Full Text] [PDF]

				N. Alessandri-Haber, O. A. Dina, E. K. Joseph, D. Reichling, and J. D. Levine A transient receptor potential vanilloid 4-dependent mechanism of hyperalgesia is engaged by concerted action of inflammatory mediators. J. Neurosci., April 5, 2006; 26(14): 3864 - 3874. [Abstract] [Full Text] [PDF]