Contrasting Signaling Pathways of 1A- and 1B-Adrenergic Receptor Subtype Activation of Phosphatidylinositol 3-Kinase and Ras in Transfected NIH3T3 Cells

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Abstract
Activation of protein kinases is an important inter- mediate step in signaling pathways of many G pro- tein-coupled receptors including a1-adrenergic re- ceptors. The present study was designed to investigate the capacity of the three cloned sub- types of human a1-receptors, namely, a1A, a1B and a1D, to activate phosphatidylinositol 3-kinase (PI 3-kinase) and p21ras in transfected NIH3T3 cells. Norepinephrine activated PI 3-kinase in cells ex- pressing human a1A and a1B via pertussis toxin- insensitive G proteins; a1D-receptors did not de- tectably activate this kinase. Transient transfection of NIH 3T3 cells with the a-subunit of the G protein transducin (at) a scavenger of bg-subunits re- leased from activated G proteins, inhibited a1B- receptor but not a1A-receptor-stimulated PI 3-ki- nase activity. Stimulation of both a1A- and a1B- receptors activated p21ras and stimulated guanine nucleotide exchange on Ras protein. Overexpres- sion of a dominant negative mutant of p21ras at- tenuated a1B-receptor but not a1A-receptor activa- tion of PI 3-kinase. Overexpression of a dominant negative mutant of PI 3-kinase attenuated a1A- but not a1B-receptor-stimulated mitogen-activated protein kinase activity. These results demonstrate the capacity for heterologous signaling of the a1- adrenergic receptor subtypes in promoting cellular responses in NIH3T3 cells. (Molecular Endocrinol-

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