Regulation of cell growth and mitogen-activated protein kinase family members by alpha-1 adrenergic receptor subtypes.

摘要

An underlying pathology of advanced cardiovascular disease is the abnormal growth of heart and vascular muscle. A principal mediator of this growth response is the alpha-1 adrenergic receptor (α₁-AR). Three genes encoding unique α₁-AR subtypes have been cloned and are referred to as the α_1A-, α_1B-, or α_1D-AR subtype. The functions of each subtype in cell growth regulation have yet to be fully elucidated. The purpose of this research was to characterize the type of growth response mediated by each receptor subtype and determine the roles of growth-regulatory mitogen-activated protein kinase (MAPK) family members in mediating the growth response.; These studies show that stimulation of each α₁-AR subtype results in a similar pattern of cell growth responses. [3H]Thymidine incorporation, an indicator of DNA synthesis and cell proliferation, was decreased following treatment with the α₁-AR agonist phenylephrine (PE) with a rank order of α_1D > α_1B = α _1A. In contrast, PE increased protein synthesis, as assessed by [ 35S]methionine incorporation, in each cell line with a rank order of α_1B > α_1A = α_1D. The α _1D-AR cells exhibited high-basal protein synthesis compared to the α _1A- and α_1B-expressing cells.; The abilities of the receptor subtypes to activate MAPK family members were clearly diverse. The α_1A-AR activated extracellular signal-regulated kinase (ERK1/2), Jun N-terminal kinase (JNK), and p38 kinase; the α_1B-AR activated ERK1/2 and p38 kinase; and the α _1D-AR activated ERK1/2 and JNK. The α_1D-AR cell line exhibited high basal (ERK1/2), activity that was decreased with the inverse agonist prazosin, suggesting this subtype is constitutively active with respect to ERK1/2 activation.; Selective inhibitors of MAPKs demonstrated that inhibition of DNA synthesis in α_1B-AR cells was mediated, at least in part, by p38 kinase. Maximal [35S]methionine incorporation in α_1A- and α_1B-AR cells required both ERK1/2 and p38 kinase activity. Elevated basal protein synthesis in the α_1D-AR cell line was reduced by inhibition of (ERK1/2), activation, suggesting a link between constitutive activity, ERK1/2 activation, and protein synthesis.; In conclusion, the results indicate that α₁-AR subtypes mediate similar growth responses but have different requirements of MAPK family member activation. The α_1D-AR subtype exhibited constitutive activity with respect to ERK1/2 activation and protein synthesis.