STKE: When a Tug Is As Good As a Ligand

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Science  18 Jun 2004:
Vol. 304, Issue 5678, pp. 1721b
DOI: 10.1126/science.304.5678.1721b

Mechanical stress on the heart due to 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. 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 caused activation of the mitogen-activated protein kinases ERK1 and ERK2 only if the 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 could not bind AII. In ATG−/− mice, which 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, being physically stretched into an active conformation, or whether some other associated molecule might provide an activating signal. — LBR

Nature Cell Biol. 6, 499 (2004).

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