Angiotensin receptors and norepinephrine neuromodulation: implications of functional coupling

The objective of this review is to examine the role of neuronal angiotensin II (Ang II) receptors in vitro. Two types of G protein-coupled Ang II receptors have been identified in cardiovascularly relevant areas of the brain: the AT 1 and the AT 2. We have utilized neurons in culture to study the signaling mechanisms of AT 1 and AT 2 receptors. Neuronal AT 1 receptors are involved in norepinephrine (NE) neuromodulation. NE neuromodulation can be either evoked or enhanced. Evoked NE neuromodulation involves AT 1 receptor-mediated, losartan-dependent, rapid NE release, inhibition of K + channels and stimulation of Ca 2+ channels. AT 1 receptor-mediated enhanced NE neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an increase in NE transporter, tyrosine hydroxylase and dopamine β-hydroxylase mRNA transcription. Neuronal AT 2 receptors signal via a G i protein and are coupled to activation of PP2A and PLA 2 and stimulation of K + channels. Finally, putative cross-talk pathways between AT 1 and AT 2 receptors will be discussed.