Cardiac-specific overexpression of alpha1BAR regulates betaAR activity via molecular crosstalk.
alpha1AR play an important role in regulating cardiac contractility under many physiological and pathological conditions. We are thus interested in determining the molecular events coupled to alpha1AR signalling pathways in the heart and in the possibility of molecular crosstalk between different receptor systems. We have analysed transgenic mouse lines which overexpress the wild-type (WT) alpha1BAR (3.0+/-0.26 pmol/mg, TgA and 2.1+/-0.26 pmol/mg, TgB) compared to non-transgenic animals (0.02+/-0.002 pmol/mg). Ligand binding studies showed that overexpression of alpha1BAR did not affect the betaAR density or their affinity for a specific antagonist. Basal adenylyl cyclase activity, but not basal cAMP levels, was increased in the transgenic animals, while isoproterenol-mediated fold stimulation of adenylyl cyclase activity of both transgenic mouse lines was decreased significantly. In addition, high-affinity betaAR agonist binding was severely impaired in the transgenic animals. We found increases in the amount of two Ca2+-independent (delta and epsilon) and one Ca2+-dependent (betaII) protein kinase (PKC) isoforms associated with the particulate fraction, suggesting that PKC may be involved in the heterologous desensitization of betaAR by alpha1BAR. These results indicate that following alpha1BAR overexpression, the betaAR system may be uncoupled via molecular crosstalk.
Institut de cardiologie de Montréal et le Groupe de Recherche sur le Système Nerveux Autonome, Université de Montréal, Canada.
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I
Lemire
B G
BG
Allen
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Rindt
T E
TE
Hebert
D000318:Adrenergic beta-Agonists / Q000378:metabolism; D000818:Animals; D015870:Gene Expression; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000378:metabolism; D007545:Isoproterenol / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*
C547717:Adra1b protein, mouse; D000318:Adrenergic beta-Agonists; D007527:Isoenzymes; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D011493:Protein Kinase C; D007545:Isoproterenol