| Autor: |
Bawa-Khalfe, Tasneem, Altememi, Ghazi F., Mandyam, Chitra D., Schwarz, Lindsay A., Eikenburg, Douglas C., Standifer, Kelly M. |
| Předmět: |
|
| Zdroj: |
BMC Pharmacology; 2007, Vol. 7, p16-27, 12p |
| Abstrakt: |
Background: In addition to the regulation of blood pressure, α2- and β-adrenoceptor (AR) subtypes play an important role in the modulation of noradrenergic neurotransmission in the human CNS and PNS. Several studies suggest that the α2-AR responsiveness in cells and tissues after chronic epinephrine (EPI) or norepinephrine (NE) exposure may vary, depending on the β-AR activity present there. Recently, we reported that in BE(2)-C human neuroblastoma cells (endogenously expressing α2A- and β2-AR), chronic EPI treatment (300 nM) produced a dramatic β-adrenoceptor-dependent desensitization of the α2A-AR response. The aim of this study is to determine if stable addition of a β2-AR to a second neuroblastoma cell line (SH-SY5Y), that normally expresses only α2A-ARs that are not sensitive to 300 nM EPI exposure, would suddenly render α2A-ARs in that cell line sensitive to treatment with the same EPI concentration. Methods: These studies employed RT-PCR, receptor binding and inhibition of cAMP accumulation to confirm α2-AR subtype expression. Stable clones of SH-SY5Y cells transfected to stably express functional β2-ARs (SHβ2AR4) were selected to compare sensitivity of α2-AR to EPI in the presence or absence of β2-ARs. Results: A series of molecular, biochemical and pharmacological studies indicated that the difference between the cell lines could not be attributed to α2-AR heterogeneity. We now report that after transfection of functional β2-AR into SH-SY5Y cells (SHβ2AR4), chronic treatment with modest levels of EPI desensitizes the α2A-AR. This effect results from a β2-AR dependent downregulation of native α2A-ARs by EPI accompanied by enhanced translocation of GRK2 and GRK3 to the membrane (required for GRK-mediated phosphorylation of agonist-occupied receptors). Conclusion: This study further supports the hypothesis that the presence of the β-AR renders the α2A-AR more susceptible to desensitization with physiological levels of EPI. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
Full text from SpringerLink