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Volume 16, Number 13, Issue of July 1, 1996 pp. 4047-4058
Copyright ©1996 Society for Neuroscience

Regulation of Neuromodulatory Actions of Angiotensin II in the Brain Neurons by the Ras-Dependent Mitogen-Activated Protein Kinase Pathway

Received Dec. 12, 1995; revised Feb. 20, 1996; accepted March 4, 1996.

Hong Yang, Di Lu, Kan Yu, and Mohan K. Raizada

Department of Physiology, University of Florida, College of Medicine, Gainesville, Florida 32610

Angiotensin II (Ang II) stimulates norepinephrine transporter (NET) and tyrosine hydroxylase (TH) in the neurons, but the signal transduction mechanism of this neuromodulation is not understood. Treatment of neuronal cultures of hypothalamus-brainstem with Ang II resulted in a time- and dose-dependent activation of Ras, Raf-1, and mitogen-activated protein kinase. This activation was mediated by the interaction of Ang II with the AT1 receptor subtype and was associated with the redistribution of AT1 receptor with Ras and Raf-1 on the neuronal membrane. Treatment with antisense oligonucleotide (AON) to mitogen-activated protein kinase decreased mitogen-activated protein kinase immunoreactivity by 70% and attenuated Ang II stimulation of c-fos, NET, and TH mRNA levels. This demonstrates that induction of these genes requires mitogen-activated protein kinase activation by Ang II. In contrast, AON to mitogen-activated protein kinase failed to inhibit Ang II stimulation of plasminogen activator inhibitor-1 mRNA levels. These results suggest that AT1 receptors are coupled to a Ras-Raf-1 mitogen-activated protein kinase signal transduction pathway that is responsible for stimulation of NET and TH, two neuromodulatory actions of Ang II in the brain.

Key words: Ras; Raf-1; MAP kinase; angiotensin II; neurons; neuronal cultures; antisense; brain AT1 receptor; norepinephrine transporter; tyrosine hydroxylase; mRNA




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