Abstract
Three distinct subtypes of alpha(1)-adrenergic receptors (alpha(1)A-, alpha(1)B-, and alpha(1)D-AR) play a prominent role in cell growth. However, little is known about subtype-specific effects on cell proliferation. The activation of alpha(1)A- or alpha(1)B-AR inhibits serum-promoted cell proliferation, whereas alpha(1)D-AR activation does not show such an inhibitory effect. Notably, cell-cycle progression was blocked at G(1)/S transition after activation of alpha(1)A/alpha(1)B-AR but not of alpha(1)D-AR. In agreement with the differential cell proliferation effect, cAMP production was increased after activation of alpha(1)A/alpha(1)B-AR but not alpha(1)D-AR, whereas all alpha(1)-AR subtypes are associated with inositol 1,4,5-trisphosphate production and mitogen-activated protein kinase activation in a similar fashion. Furthermore, the serum-induced reduction in the levels of the cyclin-dependent kinase inhibitor, p27(Kip1), was blocked after activation of alpha(1)A/alpha(1)B-AR but not alpha(1)D-AR. These results show that alpha(1)-AR subtypes differentially activate the cAMP/p27(Kip1) pathway and thereby have differential inhibitory effects on cell proliferation. Subtype-dependent effects should be taken into consideration when assessing the physiological response of native cells where alpha(1)-AR subtypes are generally co-expressed.
Highlights
There is substantial evidence indicating that stimulation of ␣1-ARs by catecholamines generally enhances growth-related gene expression and cell growth in a variety of cells including cardiac myocytes, vascular smooth muscle cells, hepatocytes, and adipocytes (4 – 6)
Activation of ␣1A- or ␣1B-AR but not ␣1D-AR Inhibits Serumpromoted Cell Cycle Progression—To explore the mechanism underlying the ␣1-AR subtype-dependent differential effects on DNA synthesis and morphological alterations, the effects of ␣1-AR activation on the cell cycle progression were examined by flow cytometric analysis in each of the CHO cell lines
We explored the roles of each ␣1-AR subtype in cell proliferation using a heterologous expression system
Summary
There is substantial evidence indicating that stimulation of ␣1-ARs by catecholamines generally enhances growth-related gene expression and cell growth in a variety of cells including cardiac myocytes, vascular smooth muscle cells, hepatocytes, and adipocytes (4 – 6). Activation of ␣1A-AR or ␣1B-AR but Not ␣1D-AR Inhibits Serum-stimulated Cell Proliferation—The cell proliferation of CHO cells stably expressing each ␣1-AR subtype (CHO␣1A, CHO␣1B, and CHO␣1D) was measured by [3H]thymidine incorporation after serum deprivation. The activation of ␣1-AR by phenylephrine (10 M) inhibited the serum-promoted [3H]thymidine incorporation in CHO␣1A and CHO␣1B cells, whereas such an inhibitory effect was not observed when treating CHO␣1D cells with phenylephrine (Fig. 1).
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