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The Journal of Neuroscience, April 1, 1999, 19(7):2413-2423
Role of Phosphatidylinositol 3-Kinase in Angiotensin II
Regulation of Norepinephrine Neuromodulation in Brain Neurons of the
Spontaneously Hypertensive Rat
Hong
Yang and
Mohan K.
Raizada
Department of Physiology, College of Medicine, and University of
Florida Brain Institute, Gainesville, Florida 32610
Chronic stimulation of norepinephrine (NE) neuromodulation by
angiotensin II (Ang II) involves activation of the Ras RafMAP kinase
signal transduction pathway in Wistar Kyoto (WKY) rat brain neurons.
This pathway is only partially responsible for this heightened action
of Ang II in the spontaneously hypertensive rat (SHR) brain neurons. In
this study, we demonstrate that the MAP kinase-independent signaling
pathway in the SHR neuron involves activation of PI3-kinase and protein
kinase B (PKB/Akt). Ang II stimulated PI3-kinase activity in both WKY
and SHR brain neurons and was accompanied by its translocation from the
cytoplasmic to the nuclear compartment. Although the magnitude of
stimulation by Ang II was comparable, the stimulation was more
persistent in the SHR neuron compared with the WKY rat neuron.
Inhibition of PI3-kinase had no significant effect in the WKY rat
neuron. However, it caused a 40-50% attenuation of the Ang II-induced
increase in norepinephrine transporter (NET) and tyrosine hydroxylase
(TH) mRNAs and [3H]-NE uptake in the SHR neuron.
In contrast, inhibition of MAP kinase completely attenuated Ang II
stimulation of NET and TH mRNA levels in the WKY rat neuron, whereas it
caused only a 45% decrease in the SHR neuron. However, an additive
attenuation was observed when both kinases of the SHR neurons were
inhibited. Ang II also stimulated PKB/Akt activity in both WKY and SHR
neurons. This stimulation was 30% higher and lasted longer in the SHR
neuron compared with the WKY rat neuron. In conclusion, these
observations demonstrate an exclusive involvement of
PI3-kinase-PKB-dependent signaling pathway in a heightened NE
neuromodulatory action of Ang II in the SHR neuron. Thus, this study
offers an excellent potential for the development of new therapies for
the treatment of centrally mediated hypertension.
Key words:
PI3-kinase; protein kinase B; angiotensin; neuromodulation; spontaneously hypertensive rat; neuron
Copyright © 1999 Society for Neuroscience 0270-6474/99/1972413-11$05.00/0
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