Receptors and Signal Transduction

Angiotensin II binds to two different receptors, which are referred to as AT1 and AT2 receptors. The AT1 receptor accounts for most of the peripheral and cerebral effects of angiotensin II, including cardiovascular regulation, hormone secretion and fluid balancing. Blockade of the AT1 receptor inhibits angiotensin II-induced changes in blood pressure and prevents the induction of drinking behavior. The AT1 receptor consists of a monomer of 359 amino acids. The receptor possesses seven transmembrane domains and is coupled to G proteins. Two subtypes (AT1 a and AT1 b) have been characterized.

Binding of angiotensin II to the AT1 receptor results in an activation of G proteins and involves the activation of tyrosine kinases and phospholipase C (PLCy), which cleaves phosphatodylinositol-4,5-bisphosphate to diacylglycerol (DAG) and inositol-1,4,5-trisphospate (IP3). The increase in IP3 triggers an increase in intracellular calcium. DAG activates proteinkinase C which, in turn, phosphorylates a variety of intracellular proteins (Fig. 4.9).

The AT2 receptor is also capable of binding angiotensin II. The functional significance of this receptor is not fully understood, but it might be involved in angiogenesis and the regulation of cerebral blood flow. AT2 receptors are highly expressed in neonatal tissue. AT2 levels decrease sharply after birth, but persist into adulthood in the brain and in some other tissues in rats. Additional findings have led to the proposal that the AT2 receptor might be involved in differentiation, development and/or apoptosis.

Recently it was demonstrated that, in neurons cultured from newborn hypothalamus and brain stem of rats, angiotensin II contributes to apoptosis via AT2 receptors and activation of a serine/threonine phosphatase.

As with the AT1 receptor, the AT2 receptor shows a monomeric structure. The AT2 receptor is composed of 363 amino acids and its sequence displays a homology of about 34% with the amino acid sequence of the AT1 receptor.

The AT2 receptor seems to be coupled to G proteins and exhibits the same topology.

Fig. 4.9 Schematic drawing of an AT1 receptor and the intracellular signal cascade which is activated after the binding of angiotensin II to the receptor.

Binding sites for angiotensin IV are also widely distributed in peripheral tissues as well as in the brain. Specific binding sites for angiotensin IV are found in both neurons and astrocytes. These binding sites are referred to as AT4 receptors.

By protein purification and peptide sequencing, the AT4 receptor was identified in 2001 to be identical with insulin-regulated aminopeptidase and, thus, the known angiotensin AT4 ligands are potent, competitive inhibitors of insulin-regulated aminopeptidase. The signaling cascade, activated after the binding of angiotensin IV to the AT4 receptor, is largely unknown. AT4 activation has been shown to stimulate expression and release of plasminogen activator inhibi-tor-1 (PAI-1), an effect which can be blocked by AT4 antagonists. In addition to angiotensin IV, hemorphins, a class of endogenous peptides obtained by hydro-

Fig. 4.10 Several inhibitors can interfere with the biosynthesis of angiotensin. In addition, several antagonists are available to block selectively one receptor type (losartan, PD 123319, CGP-42112A or divalinal) or both angiotensin II receptors (saralasin).
Table 4.1 Localization of AT1, AT2 and AT4 receptors in the brain, as determined by immunohistochemistry and autoradiography. Abbreviations: NTS: nucleus of the tractus solitarius; OVLT: organum vasculosum of the laminae terminalis.

Area/receptor

AT1

AT2

AT4

Cortex

Frontal and parietal cortex

+

Piriform cortex

+

+

Entorhinal cortex

+

+

Insular cortex

+

Cingulate cortex

+

+

Hippocampus

CA1-CA3; dentate gyrus

+

+

+

Subiculum

+

Amygdala

Lateral and basomedial nucleus

+

+

Basolateral nucleus

+

+

+

Central and medial nucleus

+

+

+

Globus pallidus

+

Caudate-putamen

+

+

Subfornical organ, OVLT

+

Lateral septal area

+

+

Medial septal area

+

+

Thalamus

Habenula

+

+

Anterior thalamus

+

+

+

Mediodorsal, ventroposterior

+

+

and centromedial thalamus

Ventrolateral thalamus

+

Lateral geniculate nucleus

+

Medial geniculate nucleus

+

Reticular nucleus

+

Zona incerta

+

Hypothalamus

Median eminence

+

Paraventricular nucleus

+

+

+

Periventricular nucleus

+

Supraoptic nucleus

+

+

+

Suprachiasmatic nucleus

+

+

Preoptic nucleus

+

+

Dorsomedial hypothalamus

+

+

Ventromedial hypothalamus

+

Arcuate nucleus

+

+

Mesencephalon

Superior colliculus

+

+

+

Inferior colliculus

+

+

Periaqueductal gray

+

+

Ventral tegmental area

+

+

Substantia nigra

+

+

Locus coeruleus

+

+

+

Pontine reticular nucleus

+

Cerebellum

+

+

Area postrema

+

NTS

+

Inferior olive

+

+

+

lysis of the beta chain of hemoglobin, can also interact with the AT4 receptor. Therefore, it might be possible that hemorphins acts as endogenous competitors of angiotensin IV.

Pharmacologically active antagonists directed to the three angiotensin receptors (ATI, AT2 and AT4) have been developed (Fig. 4.10).

In the brain, the presence of the three receptor types (ATI, AT2 and AT4, differing considerably in their location) has been described (Table 4.1).

Several studies have shown that angiotensin (1-7) does not act through angiotensin II receptors (ATI and AT2); and thus it is speculated that a specific receptor for angiotensin (1-7) might exist. A specific receptor for angiotensin (1-7) has not been identified or cloned so far. However, there are reports that the Mas proto-oncogene product may encode an angiotensin (1-7) receptor.

The existence of an AT3 receptor, as described in cultured neuroblastoma, is still questionable since neither specific agonists nor specific functions have been attributed to this putative receptor.

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