Invited reviewAngiotensin II receptors in the human brain1
Introduction
The renin–angiotensin system was initially described as a circulating humoral system influencing blood pressure and fluid and electrolyte homeostasis through effects on vascular smooth muscle, the adrenal cortex and the kidney [1]. It is now known that a tissue-based system also exists in many regions, including the vasculature, heart, kidney, adrenal gland, ovaries, placenta and brain, with actions largely complementary to those of the systemic peptide 2, 3, 4.
Most available evidence indicates that the brain is capable of synthesizing angiotensin peptides [5]. All components of the renin–angiotensin system are present in the brain, although some doubt remains about renin which, if present, occurs in very low concentrations [2]. The distribution of the various renin–angiotensin system components in the brain, however, raises questions about how angiotensin II is generated by neurons. For example, angiotensinogen is synthesized by astrocytes [5], indicating that a mechanism must exist for the transfer of angiotensinogen, or a metabolite, from astrocytes to neurons. As mentioned, renin, if present, is in such low concentrations that it has proved difficult to determine its location. Angiotensin converting enzyme is widely distributed in the brain and is probably involved in processing substrates other than just angiotensin I [6]. The distribution of angiotensin-like immunoreactivity in nerve terminals is well defined [7]and has a very high correlation with the distribution of angiotensin AT1 and AT2 receptors, defined by in vitro autoradiography with 125I-[Sar1, Ile8] angiotensin II, or by in situ hybridization histochemistry 8, 9. In addition, angiotensin receptors and angiotensin-like immunoreactive nerve terminals occur in sites where microinjections of angiotensin II produce changes in physiological parameters such as blood pressure, drinking behaviour, salt appetite and neuroendocrine function [10]. These latter observations provide strong support for the contention that angiotensin acts in the brain as a neurotransmitter or neuromodulator.
Whilst multiple angiotensin receptor subtypes have been postulated, only three, the AT1A, AT1B and the AT2, receptors have been cloned 11, 12, 13, 14. The human has only one form of the AT1 receptor [15]. Both AT1 and AT2 receptors belong to the G-protein-coupled, seven transmembrane-spanning domain family of receptors, but they share only 32% homology in amino acid sequence 11, 12, 14. The AT1 receptor, which mediates most of the known functions of angiotensin II, including effects on the cardiovascular system and fluid and electrolyte homeostasis [16], associates with Gq. Activation of the AT1 receptor stimulates phospholipase C-mediated pathways, mitogen-activated protein kinases and protein tyrosine phosphorylation 17, 18, 19. The actions of the AT2 receptor and its intracellular signalling pathways are being elucidated. The AT2 receptor associates with the Gai protein family and is known to inhibit mitogen-activated protein kinase activity and protein phosphatase 2A and stimulate potassium channel activity 20, 21, 22, 23. The AT2 receptor is expressed in very high levels in the developing animal in mesenchymal cells, leading to the postulation that, through the AT2 receptor, angiotensin would have effects on growth [24]. Indeed, AT2 receptor stimulation induces apoptosis [25]. Interestingly, AT2 receptor knock-out mice show no major morphological abnormalities but display alterations in blood pressure control and behaviour 26, 27.
In addition to the AT1 and AT2 receptors, AT4 binding sites, which specifically bind angiotensin 3–8, have also been characterized, but not cloned [28]. The distribution of the AT4 receptor has been mapped in the brain of several mammals 28, 29, 30, but not humans, and will not be discussed further in this review.
Section snippets
The distribution of angiotensin (Ang) receptors
The distributions of Ang II AT1 and AT2 receptors have been mapped in the central nervous system of several mammals 8, 31, 32, 34, including the human [33]. Whilst the distribution of the AT1 receptor is highly conserved between species, the AT2 receptor shows considerable variation. This is most striking for the human brain, where we have been able to detect AT2 receptors only in the cerebellar cortex [33]. Another study has suggested that the distribution of AT2 receptors in the human nervous
Conclusion
Mapping the distribution of Ang II AT1 and AT2 receptors in the human brain has yielded valuable new information from which inferences can be made regarding the role of Ang II in the human central nervous system. We demonstrate that AT1 receptors occur in many nuclei that are homologues of those expressing the receptor in experimental animals and, in many cases, for which physiological functions of Ang II have been ascribed. Indeed, the correlation between the distributions of AT1 receptors in
Acknowledgements
The work contained in this review was supported by grants from the National Health and Medical Research Council of Australia, the National Heart Foundation of Australia, the National SIDS Foundation and the Ian Potter Foundation.
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100 years of Renin.