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Contrasting Signaling Pathways of _1A- and _1B-Adrenergic Receptor Subtype Activation of Phosphatidylinositol 3-Kinase and Ras in Transfected NIH3T3 Cells

Geriatric Research, Education and Clinical Center Veterans Affairs Palo Alto Health Care System Palo Alto, California 94304
Department of Medicine Stanford University School of Medicine Stanford, California 94305

Activation of protein kinases is an important intermediate step in signaling pathways of many G protein-coupled receptors including ₁-adrenergic receptors. The present study was designed to investigate the capacity of the three cloned subtypes of human ₁-receptors, namely, _1A, _1B and _1D, to activate phosphatidylinositol 3-kinase (PI 3-kinase) and p21^ras in transfected NIH3T3 cells. Norepinephrine activated PI 3-kinase in cells expressing human _1A and _1B via pertussis toxin-insensitive G proteins; _1D-receptors did not detectably activate this kinase. Transient transfection of NIH 3T3 cells with the -subunit of the G protein transducin (_t) a scavenger of ß-subunits released from activated G proteins, inhibited _1B-receptor but not _1A-receptor-stimulated PI 3-kinase activity. Stimulation of both _1A- and _1B-receptors activated p21^ras and stimulated guanine nucleotide exchange on Ras protein. Overexpression of a dominant negative mutant of p21^ras attenuated _1B-receptor but not _1A-receptor activation of PI 3-kinase. Overexpression of a dominant negative mutant of PI 3-kinase attenuated _1A- but not _1B-receptor-stimulated mitogen-activated protein kinase activity. These results demonstrate the capacity for heterologous signaling of the ₁-adrenergic receptor subtypes in promoting cellular responses in NIH3T3 cells.

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