The active peptide in the renin-angiotensin system (RAS) is angiotensin II (Ang II), which exerts its effects by binding to a receptor on the cell surface. There are four known types of Ang II receptor, which were first classified based on their sensitivity to certain pharmacological agents – sartans and PD123319. The type 1 receptor is the target of anti-hypertensive drugs known as ARBs (angiotensin receptor blockers).
Two of the subtypes have been seen under only particular conditions and little is known about them. The type 3 receptor (AT3) is from a mouse neuroblastoma cell line and is not blocked by either pharmacological agent. The type 4 receptor (AT4) does not actually bind to Ang II, but to its smaller metabolite Ang IV. This receptor was first seen in the bovine adrenal gland and may be involved in the cognitive brain functions, vasculature dilation, and counteracting some Ang II functions in the heart and kidney of other mammals.
The Angiotensin II Type 1 Receptor (AT1)
The AT1 receptor is selectively inhibited by sartans. In mammals, the receptor is 359 amino acids in length and was initially characterized from human liver. The receptor has a molecular mass of 41 KDa, though it is 65 KDa when glycosylated. Humans have one AT1; rodents have two – AT1a and AT1b. This makes some interpretations from studies in rodent models to humans difficult, though both receptor types are more than 90% homologous to the human AT1 and AT1a has been shown to be the subtype to which the human subtype is most identical.
The AT1 receptor plays an important role in Ang II signaling, which will be discussed in a later article. It is a seven transmembrane G-protein coupled receptor. When Ang II binds, it results in a conformational change that activates a signal cascade, by acting as a scaffold for signaling proteins, resulting in the regulation of tyrosine kinase activity. The AT1 receptor mediates most of the known physiological actions of Ang II, including the regulation of arterial blood pressure, water balance, hormone secretion, and renal function. However, there is a relatively low abundance of the receptor in Ang II target tissues, but it is found to some extent in the heart, kidney, liver, brain, endometrium, vascular smooth muscle cells, lung macrophages, and adrenals.
Angiotensin II Type 2 Receptor (AT2)
The AT2 receptor is inhibited by PD123319 and related compounds; it shares only 32-34% homology with AT1, though they both bind Ang II. The AT2 receptor is expressed widely in fetal tissues, and it is restricted after birth to the brain, adrenals, heart, kidney, myometrium, and ovary; but predominantly in mesenchymal tissues in the tongue, skin, and diaphragm. The number of these receptors is increased in the case of vascular injury, myocardial infarction, congestive heart failure, renal failure, brain ischemia, and nerve transsection.
Some research has suggested that the AT2 receptor keeps the AT1 receptor’s actions in balance by resulting in the opposite effects upon Ang II binding. Activation of AT2 results in vasodilation and natriuresis. Unlike AT1, AT2 receptors signal through Gi protein coupling and phosphatase activation. However, this counteraction has not been seen in the central responses in the brain.
References
de Gasparo et al. International Union of Pharmacology. XXIII. The Angiotensin II Receptors. Pharmacol Rev 52: 415-472, 2000.
Inagami et al. Molecular biology of angiotensin II receptors: an overview. J Hypertens 12 (suppl 10): S83-S94, 1994.
Inagami. Molecular biology and signaling of angiotensin receptors: an overview. J Am Soc Nephrol 10: S2-S7, 1999.
Kaschina and Unger. Angiotensin AT1/AT2 receptors: regulation, signalling, and function. Blood Pressure 12: 70-88, 2003.
Nawata et al. Type 1 angiotensin II receptors of adrenal tumors. Steroids 60: 28-34, 1995.
