[Molecular structure and function of angiotensin ii receptors]. / Structure et fonctions moléculaires des récepteurs de l'angiotensine II.

ABSTRACT

Angiotensin II (Ang II) receptors are 7 transmembrane domain receptors corresponding to 2 pharmacologically and molecularly distinct receptors, called AT1 and AT2, the primary structures of which have been established by molecular cloning. Most if not all the physiological actions of Ang II are mediated by the AT1 receptor, which is coupled to a Gq protein activating a phospholipase C (PLC), which in turn mobilizes the intracellular calcium stores and activates protein kinases C. Many site directed mutagenesis works have allowed to identify short extracellular sequences responsible for the Ang II binding, whereas non-peptidic AT1-specific antagonists bind to a different transmembranar site. Structural modifications are responsible for the change of the receptor from an inactive to an active state. At the basal state, the receptor is mostly in an inactive state; agonists present a better affinity for the active state, displacing the equilibrium to this state; at the opposite, the inverse agonists present a better affinity for the inactive state. Antagonists present a similar affinity for both states of the receptor. Several mutations of polar residues of the transmembrane domains block the receptor either in an inactive state (D74D, S115A, Y292F) or in a constitutively active state (N111A and N295A). After activation, the receptor is coupled to different intracellular proteins, the first of them being the G proteins of the Gq/11 family. The sequences of the receptor involved in this coupling correspond to the 2nd, the 3rd intracellular loops and the proximal segment of the carboxyterminal domain. Other sequences interact with other proteins, such as the 319YIPP332 sequence of the carboxyterminus, which interacts with the Jak2 tyrosine kinase. After the binding of a peptidic ligands, the ligand-receptor complex is internalized independently for the G protein coupling. Again, site directed mutagenesis experiments have localized a sequence of the carboxyterminus (329STLSTKMSTLS338) involved in the internalization. This serine and threonine-rich sequence plays also a role in the desensitization of the AT1 receptor, consecutively to its phosphorylation. The AT2 receptor is only 34% identical to the AT1 receptor and its functions are far less understood. Its physiological functions (apoptosis and antiproliferative actions) and its signaling pathways (activation of Gi proteins and tyrosine phosphatases) are still a matter of debate.