α1-adrenergic receptor subtypes differentially control the cell cycle of transfected CHO cells through a cAMP-dependent mechanism involving p27Kip1

Abstract

Three distinct subtypes of α1-adrenergic receptors (α1A-, α1B-, and α1D-AR) play a prominent role in cell growth. However, little is known about subtype-specific effects on cell proliferation. The activation of α1A- or α1B-AR inhibits serum-promoted cell proliferation, whereas α1D-AR activation does not show such an inhibitory effect. Notably, cell-cycle progression was blocked at G1/S transition after activation of α1A/α1B-AR but not of α1D-AR. In agreement with the differential cell proliferation effect, cAMP production was increased after activation of α1A/α1B-AR but not α1D-AR, whereas all α1-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, p27Kip1, was blocked after activation of α1A/α1B-AR but not α1D-AR. These results show that α1-AR subtypes differentially activate the cAMP/p27Kip1 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 α1-AR subtypes are generally co-expressed.