A novel player in cellular hypertrophy: Giβγ/PI3K-dependent activation of the RacGEF TIAM-1 is required for α₁-adrenoceptor induced hypertrophy in neonatal rat cardiomyocytes

Journal of Molecular and Cellular Cardiology
Christiane VettelThomas Wieland

Abstract

Activation of α(1)-adrenoceptors (α(1)-AR) by high catecholamine levels, e.g. in heart failure, is thought to be a driving force of cardiac hypertrophy. In this context several downstream mediators and cascades have been identified to potentially play a role in cardiomyocyte hypertrophy. One of these proteins is the monomeric G protein Rac1. However, until now it is unclear how this essential G protein is activated by α(1)-AR agonists and what are the downstream targets inducing cellular growth. By using protein-based as well as pharmacological inhibitors and the shRNA technique, we demonstrate that in neonatal rat cardiomyocytes (NRCM) Rac1 is activated via a cascade involving the α(1A)-AR subtype, G(i)βγ, the phosphoinositide-3'-kinase and the guanine nucleotide exchange factor Tiam1. We further demonstrate that this signaling induces an increase in protein synthesis, cell size and atrial natriuretic peptide expression. We identified the p21-activated kinase 2 (PAK2) as a downstream effector of Rac1 and were able to link this cascade to the activation of the pro-hypertrophic kinases ERK1/2 and p90RSK. Our data thus reveal a prominent role of the α(1A)-AR/G(i)βγ/Tiam1-mediated activation of Rac1 and its effector PAK2 in the in...Continue Reading

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Citations

Nov 17, 2012·Biochimica Et Biophysica Acta·K M HannanR B Pearson
Mar 12, 2015·Cellular Microbiology·Markus WeiseJoachim H C Orth
Apr 30, 2015·Acta Biochimica Et Biophysica Sinica·Lanfang LiZhisheng Jiang
Mar 1, 2014·Channels·Brant E Isakson, Roger J Thompson
Dec 20, 2014·Nitric Oxide : Biology and Chemistry·Min LiangYi-Chun Zhu
Oct 26, 2013·Circulation Research·Christopher C Glembotski
Jun 17, 2018·EMBO Molecular Medicine·András D TóthJohannes Backs
Jul 28, 2013·The Journal of Pharmacology and Experimental Therapeutics·Magdolna LevayThomas Wieland
Sep 2, 2020·American Journal of Hypertension·Fu-Han GongWen-Lin Cheng
Jun 15, 2014·Pharmacological Reviews·Andrea Ahles, Stefan Engelhardt

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