Abstract
α2-Adrenergic receptor (α2-AR) activation in the pregnant rat myometrium at midterm potentiates β2-AR stimulation of adenylyl cyclase (AC) via Gβγ regulation of the type II isoform of adenylyl cyclase. However, at term, α2-AR activation inhibits β2-AR stimulation of AC. This phenomenon is associated with changes in α2-AR subtype expression (midterm α2A/D-AR ≫ α2B-AR; term α2B ≥ α2A/D-AR), without any change in ACII mRNA, suggesting that α2A/D- and α2B-AR differentially regulate β2-cAMP production. To address this issue, we have stably expressed the same density of α2A/D- or α2B-AR with AC II in DDT1-MF2 cells. Clonidine (partial agonist) increased β2-AR-stimulated cAMP production in α2A/D-AR-ACII transfectants but inhibited it in α2B-AR-ACII transfectants. In contrast, epinephrine (full agonist) enhanced β2-stimulated ACII in both α2A- and α2B-ACII clonal cell lines. 4-Azidoanilido-[α-32P]GTP-labeling of activated G proteins indicated that, in α2B-AR transfectants, clonidine activated only Gi2, whereas epinephrine, the full agonist, effectively coupled to Gi2 and Gi3. Thus, partial and full agonists selectively activate G proteins that lead to drug specific effects on effectors. Moreover, these data indicate that Gi3 activation is required for potentiation of β2-AR stimulation of AC by α2A/D and α2B-AR in DDT1-MF2 cells. This may reflect an issue of the amount of Gβγ released upon receptor activation and/or βγ composition of Gi3 versus Gi2.
Footnotes
- Received July 26, 2000.
- Accepted October 4, 2000.
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Send reprint requests to: Isabelle Limon-Boulez, Université Pierre et Marie Curie, CNRS ESA 7080, Laboratoire de Physiologie de la Reproduction, 4 place Jussieu, 75252 Paris Cedex 05, France. E-mail: isabelle.limon-boulez{at}snv.jussieu.fr
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This work was supported by the Centre National de la Recherche Scientifique and by National Institutes of Health Grants DK53981 (T.W.G.) and MH59931 (S.M.L.).
- The American Society for Pharmacology and Experimental Therapeutics
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