alpha(1A)-Adrenoceptors activate mTOR signalling and glucose uptake in cardiomyocytes

作者：Sato Masaaki; Evans Bronwyn A; Sandstrom Anna L; Chia Ling Yeong; Mukaida Saori; Bui San Thai; Anh Nguyen; Lim Linzi; Tan Christina Y R; Baltos Jo Anne; White Paul J; May Lauren T; Hutchinson Dana S; Summers Roger J; Bengtsson Tore^*

来源：Biochemical Pharmacology, 2018, 148: 27-40.

DOI：10.1016/j.bcp.2017.11.016

• alpha(1A)-Adrenoceptor
• Cardiomyocytes
• mTOR
• AMPK
• Glucose uptake

The capacity of G protein-coupled receptors to modulate mechanistic target of rapamycin (mTOR) activity is a newly emerging paradigm with the potential to link cell surface receptors with cell survival. Cardiomyocyte viability is linked to signalling pathways involving Akt and mTOR, as well as increased glucose uptake and utilization. Our aim was to determine whether the am-adrenoceptor (AR) couples to these protective pathways, and increased glucose uptake. We characterised alpha(1A)-AR signalling in CHO-K1 cells co-expressing the human alpha(1A)-AR and GLUT4 (CHO alpha(1A)GLUT4myc) and in neonatal rat ventricular cardiomyocytes (NRVM), and measured glucose uptake, intracellular Ga2* mobilization, and phosphorylation of mTOR, Akt, 5' adenosine monophosphate-activated kinase (AMPK) and S6 ribosomal protein (S6rp). In both systems, noradrenaline and the alpha(1A)-AR selective agonist A61603 stimulated glucose uptake by parallel pathways involving mTOR and AMPK, whereas another alpha(1A)-AR agonist oxymetazoline increased glucose uptake predominantly by mTOR. All agonists promoted phosphorylation of mTOR at Ser2448 and Ser2481, indicating activation of both mTORC1 and mTORC2, but did not increase Akt phosphorylation. In CHO alpha(1A)GLUT4myc cells, siRNA directed against rictor but not raptor suppressed alpha(1A)-AR mediated glucose uptake. We have thus identified mTORC2 as a key component in glucose uptake stimulated by alpha(1A)-AR agonists. Our findings identify a novel link between the alpha(1A)-AR, mTORC2 and glucose uptake, that have been implicated separately in cardiomyocyte survival. Our studies provide an improved framework for examining the utility of alpha(1A)-AR selective agonists as tools in the treatment of cardiac dysfunction.

• 出版日期2018-2