Both alpha(1A)- and alpha(1B)-adrenergic receptors crosstalk to down regulate beta(1)-ARs in mouse heart: coupling to differential PTX-sensitive pathways.
Adrenergic receptors (ARs) play an important role in the regulation of cardiac function. Cardiac inotropy is primarily regulated by beta(1)-ARs. However, alpha(1)-ARs may play an important role in inotropy during heart failure. Previous work has suggested that the alpha(1B)-AR modulates beta(1)-AR function in the heart. The potential role of the alpha(1A)-AR has not been previously studied. We used transgenic mice that express constitutively active mutant (CAM) forms of the alpha(1A)-AR or alpha(1B)-AR regulated by their endogenous promoters. Expression of the CAM alpha(1A)-AR or CAM alpha(1B)-AR had no effect on basal cardiac function (developed pressure, +dP/dT, -dP/dT, heart rate, flow rate). However, both alpha(1)-AR subtypes significantly decreased isoproterenol-stimulated +dP/dT. Pertussis toxin had no effect on +dP/dT in CAM alpha(1A)-AR hearts but restored +dP/dT to non-transgenic values in CAM alpha(1B)-AR hearts. Radioligand binding indicated a selective decrease in the density of beta(1)-ARs in both CAM mice. However, G-proteins, cAMP, or the percentage of high and low affinity states were unchanged in either transgenic compared with control. These data demonstrate that CAM alpha(1A)- and alpha(1B)-ARs both down regulate beta(1)-AR-mediated inotropy in the mouse heart. However, alpha(1)-AR subtypes are coupled to different beta-AR mediated signaling pathways with the alpha(1B)-AR being pertussis toxin sensitive.
Rorabaugh
Boyd R
BR
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, NB5, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Gaivin
Robert J
RJ
Papay
Robert S
RS
Shi
Ting
T
Simpson
Paul C
PC
Perez
Dianne M
DM
D000818:Animals; D002316:Cardiotonic Agents; D015536:Down-Regulation; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D037342:Pertussis Toxin / Q000494:pharmacology*; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology*; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
D002316:Cardiotonic Agents; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D037342:Pertussis Toxin; D020962:Heterotrimeric GTP-Binding Proteins; D007545:Isoproterenol