Structure and functions of the angiotensin II receptors

Angiotensin II (Ang II) receptors are 7 transmembrane domain receptors corr esponding to 2 pharmacologically and molecularly distinct receptors, called AT(1) and AT(2), the primary structures of which have been established by moleculare cloning. Most if not all the physiological actions of Ang II are mediated by the AT(1) receptor, which is coupled to a Gq protein activatin g a phospholipase C (PLC), which in turn mobilizes the intracellular calciu m stores and activates protein kinases C. Many site directed mutagenesis works have allowed to identify short extrace llular sequences responsible for the Ang ii binding, whereas non-peptidic A T(1)-specific antagonists bind to a different transmembranar site, Structural modifications are responsible for the change of the receptor fro m an inactive to an active stale. At the basal stare, the receptor is mostl y in an inactive state; agonists present a better affinity for the active s tate, displacing the equilibrium to this state; at the opposite, the invers e agonists present a better affinity for the inactive state. Antagonists pr esent a similar affinity for both states of the receptor. Several mutations of polar residues of the transmembrane domains block the receptor either i n an inactive state ((DD)-D-74, S(115)A, (YF)-F-292) Or in a constitutively active state (N(111)A and N(295)A). After activation, the receptor is coupled to different intracellular protei ns, the first of them being the G proteins of the Gq/11 family. The sequenc es 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 (YIPP332)-Y-319 sequence of the carboxyterminus, which interacts with the Jak2 tyrosine ki nase. After the binding of a peptidic ligands, the ligand-receptor complex is internalized independently for the G protein coupling. Again, site direc ted mutagenesis experiments have localized a sequence of the carboxyterminu s ((STLSTKMSTLS338)-S-329) involved in the internalization. This serine and threonine-rich sequence plays also a role in the desensitization of the AT (1) receptor, consecutively to its phosphorylation. The AT(2) receptor is only 34 % identical to the AT(1) receptor and its fun ctions are far less understood. its physiological functions (apoptosis and antiproliferative actions) and its signaling pathways (activation of Gi pro teins and tyrosine phosphatases) are still a matter of debate.