Distribution and signal transduction of angiotensin II AT1 and AT2 receptors.

The discovery of new pharmacologic and biochemical tools has prompted intensive research on the intracellular mechanisms conveying the physiologic message carried by angiotensin II (A II). Virtually all the cardiovascular effects of A II are activated by mobilization of the calcium messenger system through the AT1-receptor subtype. The AT2 subtype, which is highly expressed in fetal tissues, appears to be silent in adult tissues but may play a role in growth-related functions. Several functional domains that are involved in distinct processes have been identified in the AT1 receptor. Through a GTP-binding protein (Gq), A II activates a phospholipase C, which generates inositol 1,4,5-trisphosphate (Ins[1,4,5]P3) and diacylglycerol. Ins(1,4,5)P3 releases calcium from intracellular stores, which is a signal for a "capacitative" calcium influx. The net result of the various processes of calcium trafficking is an initial transient peak of cytosolic calcium concentration ([Ca2+]c) followed by a sustained response. A II also induces a translocation of protein kinase C (PKC) from the cytosol to the cell membrane. PKC can either potentiate or counteract the responses elicited by the [Ca2+]c changes. A II also alters the activity of voltage-gated calcium channels and of the sodium-calcium exchanger. Finally, the activity of adenylyl cyclase can also be affected. By contrast, the signaling mechanisms linked to the AT2-receptor subtype are poorly understood. The integration of these multiple and variable signals, as well as the cell's enzymatic repertory, eventually determine the specific cellular response. The unraveling of these complex mechanisms opens new perspectives for the development of therapeutic tools that could interfere more specifically with the intracellular processes of A II and its effects on the cardiovascular system.