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© The Rockefeller University Press, 0021-9525/1998//217 $5.00
The Journal of Cell Biology, Volume 142, Number 1, , 1998 217-227

Articles

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



Di Lu*, Hong Yang*, Robert H. Lenox{ddagger}, and Mohan K. Raizada*

* Department of Physiology, {ddagger} 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 β-hydroxylase (DβH), 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)β 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 PKCβ 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 DβH immunoreactivities and [3H]NE uptake activity in synaptosomes. In contrast, mRNA levels of TH, DβH, 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, DβH, and [3H]NE uptake in neuronal synaptosomes. These observations demonstrate that phosphorylation of MARCKS by PKCβ and its redistribution from varicosities to neurites is important in Ang II–induced synaptic accumulation of TH, DβH, and NE. They suggest that a coordinated stimulation of transcription of TH, DβH, and NET, mediated by Ras-Raf-MAP kinase followed by their transport mediated by PKCβ-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

Abbreviations used in this paper: Ang II, angiotensin II; AON, antisense oligonucleotide; AT1 receptor, angiotensin type 1 receptor subtype; DβH, dopamine β hydroxylase; MARCKS, myristoylated alanine-rich C kinase substrate; NE, norepinephrine; NET, norepinephrine transporter; PDHS, plasma-derived horse serum; PKC, protein kinase C; PSD, basic phosphorylation site domain in MARCKS; SON, sense oligonucleotide; TH, tyrosine hydroxylase; WKY, Wistar Kyoto.

Address all correspondence to Dr. Mohan K. Raizada, Professor and Associate Dean for Graduate Education, Department of Physiology, College of Medicine, University of Florida, PO Box 100274, Gainesville, FL 32610. Tel.: (352) 392–3791. Fax: (352) 846-0270. E-mail: mraizada{at}dean.med.ufl.edu

R.H. Lenox's present address is Department of Psychiatry, University of Pennsylvania, Philadelphia, PA.


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