Sci. STKE, 8 June 2004
RECEPTORS When a Tug Is As Good As a Ligand
Mechanical stress on the heart that results from increased blood pressure leads to hypertrophy of heart cells and increases the risk of heart failure. The effects of mechanical stress are mediated at least in part by angiotensin II type 1 (AT1) receptors, and pharmacological blockade of such receptors can limit cardiac hypertrophy and subsequent heart failure. To explore how AT1 receptors actually sense mechanical stress, Zou et al. studied cells cultured on silicone-based dishes that could be stretched to apply mechanical stress to the cells. Mechanical stretching of human embryonic kidney 293 cells or COS7 cells caused activation of the mitogen-activated protein kinases ERK1 and ERK2 only if those cells were first transfected with the AT1 receptor. This receptor activation appeared not to result from secretion of angiotensin II (AII), as previously proposed, and was observed even in cells expressing a mutant receptor with an altered binding site that does not bind AII. In ATG–/– mice, which lack the angiotensinogen gene and thus don't make AII, mechanical stress still caused hypertrophy in vivo, supporting a biologically relevant role for the mechanical stress-induced ligand-independent regulation of the AT1 receptor. It now remains to be seen whether the receptor itself is the sensor, as it is physically stretched into an active conformation, or whether some other associated molecule might provide an activating signal.
Y. Zou, H. Akazawa, Y. Qin, M. Sano, H. Takano, T. Minamino, N. Makita, K. Iwanaga, W. Zhu, S. Kudoh, H. Toko, K. Tamura, M. Kihara, T. Nagai, A. Fukamizu, S. Umemura, T. Iiri, T. Fujita, I. Komuro, Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II. Nat. Cell Biol. 6, 499-506 (2004). [Online Journal]
Citation: When a Tug Is As Good As a Ligand. Sci. STKE 2004, tw203 (2004).
Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882