Recent Advances in the Endogenous Brain Renin-Angiotensin System and Drugs Acting on It

Figure 1

Signal transduction mechanism for angiotensin receptors—AT1 and AT2. Ang II binds to the AT1 receptor and shows vasoconstrictor action through Gi- and Gq-coupled mechanisms. Gi protein-coupled mechanism involves inhibition of adenylyl cyclase and phospholipase C stimulation coupled with Gq protein which activates secondary messengers like IP3 and diacylglycerol. Ca²⁺ released from the above pathway causes vasoconstriction. Vasoconstriction is also caused by protein kinase C from diacylglycerol and cAMP (vasodilator in nature) from the adenylyl cyclase inhibitory pathway. Gq-coupled mechanism activates phospholipase A2 and D, causing generation of arachidonic acid. Ang II binds with the AT2 receptor and by negative coupling with guanylyl cyclase shows Ca²⁺ inhibition and activation of the K⁺ channel. Also, the AT2 receptor acts through phospholipase A2 and stimulates arachidonic acid release. AT2 receptor stimulation activates several phosphatases like protein tyrosine phosphatase, MAP kinase phosphatase 1 (MKP-1), SH2-domain-containing phosphatase 1 (SHP-1), and serine threonine phosphatase 2A. When this phosphatase gets activated, there is inactivation of extracellular signal-regulated kinase (ERK), which leads to potassium channel opening and inhibition of T-type Ca²⁺ channels. Abbreviations: PLA: phospholipase A; PLC: phospholipase C; PLD: phospholipase D; IP3: inositol (1;4;5) triphosphate; DAG: diacylglycerol; PKC: protein kinase C; PTP: protein tyrosine phosphatase; PP2A: serine/threonine phosphatase 2A; ERK: extracellular signal-regulated kinase.