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J. Cell Biol., Volume 142, Number 1, July 13, 1998 217-227

Regulation of Angiotensin II-induced Neuromodulation by MARCKS in Brain Neurons

Di Lu,* Hong Yang,* Robert H. Lenox,Dagger and Mohan K. Raizada*

* Department of Physiology, Dagger  Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL 32610

Angiotensin II (Ang II) exerts chronic stimulatory actions on tyrosine hydroxylase (TH), dopamine beta -hydroxylase (Dbeta H), and the norepinephrine transporter (NET), in part, by influencing the transcription of their genes. These neuromodulatory actions of Ang II involve Ras-Raf-MAP kinase signal transduction pathways (Lu, D., H. Yang, and M.K. Raizada. 1997. J. Cell Biol. 135:1609-1617). In this study, we present evidence to demonstrate participation of another signaling pathway in these neuronal actions of Ang II. It involves activation of protein kinase C (PKC)beta subtype and phosphorylation and redistribution of myristoylated alanine-rich C kinase substrate (MARCKS) in neurites. Ang II caused a dramatic redistribution of MARCKS from neuronal varicosities to neurites. This was accompanied by a time-dependent stimulation of its phosphorylation, that was mediated by the angiotensin type 1 receptor subtype (AT1). Incubation of neurons with PKCbeta subtype specific antisense oligonucleotide (AON) significantly attenuated both redistribution and phosphorylation of MARCKS. Furthermore, depletion of MARCKS by MARCKS-AON treatment of neurons resulted in a significant decrease in Ang II-stimulated accumulation of TH and Dbeta H immunoreactivities and [3H]NE uptake activity in synaptosomes. In contrast, mRNA levels of TH, Dbeta H, and NET were not influenced by MARKS-AON treatment. MARCKS pep148-165, which contains PKC phosphorylation sites, inhibited Ang II stimulation of MARCKS phosphorylation and reduced the amount of TH, Dbeta H, and [3H]NE uptake in neuronal synaptosomes. These observations demonstrate that phosphorylation of MARCKS by PKCbeta and its redistribution from varicosities to neurites is important in Ang II-induced synaptic accumulation of TH, Dbeta H, and NE. They suggest that a coordinated stimulation of transcription of TH, Dbeta H, and NET, mediated by Ras-Raf-MAP kinase followed by their transport mediated by PKCbeta -MARCKS pathway are key in persistent stimulation of Ang II's neuromodulatory actions.

Key words: MARCKS;  brain neurons;  AT1 receptors;  neuromodulation;  protein kinase C subtypes


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