Differential Extracellular Signal‐Regulated Kinases 1 and 2 Activation by the Angiotensin Type 1 Receptor Supports Distinct Phenotypes of Cardiac Myocytes

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Abstract:  The angiotensin II (AngII) type 1 receptor (AT1R) is a seven‐transmembrane receptor well established to activate extracellular signal‐regulated kinases 1 and 2 (ERK1/2) by discrete G protein‐dependent and β‐arrestin2‐dependent pathways. The biological importance of this, however, remains obscure. Application of the modified analogue [Sar1, Ile4, Ile8]‐AngII ([SII] AngII) allowed us to dissect the two pathways of ERK1/2 activation in native cardiac myocytes. Although cytosol‐retained, the β‐arrestin2‐bound pool of ERK1/2 represents an active signalling component that phosphorylates p90 Ribosomal S6 Kinase, a ubiquitous and versatile mediator of ERK1/2 signal transduction. Moreover, the β‐arrestin2‐dependent ERK1/2 signal supports intact proliferation of cardiac myocytes. In contrast to Gq‐activated ERK1/2, and in keeping with its failure to translocate to the nucleus, the β‐arrestin2‐scaffolded pool of ERK1/2 does not phosphorylate the transcription factor Elk‐1, induces no increased transcription of the immediate‐early gene c‐Fos, and does not entail myocyte hypertrophy. These results clearly demonstrate the biological significance of differential signalling by the AT1R. The opportunity to separate desirable cardiac myocyte division from detrimental hypertrophy holds promise that novel pharmacological approaches will allow targeting of pathway‐specific actions.

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