The angiotensin II receptors are cell surface proteins present in a number of tissues. The receptors bind angiotensin II, the active peptide in the renin-angiotensin system, also known as the RAS. There are four known types of angiotensin II receptor, which were first classified based on their sensitivity to certain pharmacological agents, particularly sartans and PD123319.
The Angiotensin II Type 1 Receptor (AT1)
The AT1 receptor is selectively inhibited by sartans and is the target of the angiotensin receptor blockers (ARBs) used to treat hypertension. In mammals, the receptor is 359 amino acids in length, and it 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 type 1 receptor, but rodents have two: AT1a and AT1b. This difference is important for studies that use rodent models. However, both rodent receptor types are more than 90% homologous to the human receptor, and AT1a has been shown to be the subtype to which the human subtype is most identical.
The AT1 receptor is a seven transmembrane G-protein coupled receptor. When angiotensin II binds, the receptor undergoes 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 angiotensin II, including the regulation of arterial blood pressure, fluid balance, hormone secretion, and renal function. However, there is a relatively low abundance of the receptor in angiotensin 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. The type 2 receptor shares only 32-34% homology with the type 1 receptor, though they both bind angiotensin II. The AT2 receptor is expressed widely in fetal tissues, and it is restricted after birth to the brain, adrenals, heart, kidney, myometrium, and ovaries, 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 having counter effects upon angiotensin II binding. Example, AT2 receptor activation results in vasodilation (blood pressure decrease), but AT1 receptor activation results in vasoconstriction (blood pressure increase). Also, unlike the kinases activated in AT1 signaling, AT2 receptors signal through Gi protein coupling and phosphatase activation. However, this counteraction has not been reported, to my knowledge, in the central responses in the brain.
Type 3 and 4 Receptors
Two of the receptor 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 that blocks the type 1 and type 2 receptors. The type 4 receptor (AT4) does not actually bind to angiotensin II; it binds the smaller metabolite angiotensin IV. This receptor was first seen in the bovine adrenal gland and may be involved in cognitive brain functions, vasculature dilation, and counteracting some angiotensin II functions in the heart and kidneys of other mammals.
