| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Two distinct subtypes of angiotensin II (Ang II) receptors, type 1(AT1) and type 2 (AT2), which are members of the G-protein-coupled receptor superfamily (GPCRs), have been identified.
Multiple signaling pathways link AT1 receptor to Gq-dependent inositol phosphate (IP) production and Gq-independent phospho-extracellular signal-activated kinase(p-ERK)1/2 by Ang II in the regulation of cardiovascular vasoconstriction and cell growth, respectively. An Ang II analogue, [Sar^1, Ile^4, Ile^8]Ang II, did not stimulate Gq-dependent IP production, but still activated Gq-independent p-ERK1/2 in human coronary artery smooth muscle cells as well as in a cell line that stably expressed AT^1 receptor. This activation was mostly mediated by [Sar^1, Ile^4, Ile^8]Ang II-induced Gq-independent epidermal growth factor receptor transactivation. We found that AT^1 receptor signaling shows bifurcation into functionally separate pathways.
In addition, members of the GPCRs undergo homo- and/or hetero-oligomeri
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zation to induce cell signaling. Although some of these show constitutive activation, it is not clear how such GPCRs undergo homo-oligomerization with transmembrane (TM) helix movement. We previously reported that AT2 receptor showed constitutive activation and induced apoptosis independent of its ligand, Ang II. Therefore, we analyzed the translocation and oligomerization of AT2 receptor with TM movement when the receptor induces cell signaling. Constitutively active homo-oligomerization, which was due to disulfide bonding between Cys35 in one AT2 receptor and Cys290 in another AT2 receptor, was localized in the cell membrane without Ang II stimulation and induced apoptosis without changes in receptor conformation. These results provide the direct evidence that the constitutive active homo-oligomeric GPCRs by intermolecular interaction in two extracellular loops is translocated to the cell membrane and induces cell signaling independent of receptor conformation and ligand stimulation.
Based on molecular biological studies, we found new findings on the structure and function of Ang II receptors and possible new therapeutic strategies for targeting these receptors. Less
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