α1A-Adrenoceptors activate mTOR signalling and glucose uptake in cardiomyocytes

• Published in: Biochemical pharmacology Vol. 148; pp. 27 - 40
• Main Authors: Sato, Masaaki, Evans, Bronwyn A., Sandström, Anna L., Chia, Ling Yeong, Mukaida, Saori, Thai, Bui San, Nguyen, Anh, Lim, Linzi, Tan, Christina Y.R., Baltos, Jo-Anne, White, Paul J., May, Lauren T., Hutchinson, Dana S., Summers, Roger J., Bengtsson, Tore
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-02-2018
• Subjects: AMPK; Cardiomyocytes; Glucose uptake; mTOR; α1A-Adrenoceptor; UBO; PLC; S6rp; PKC; Cardiomyocytes; CHO; DAG; IP3; AR; Oxy; CaMKK; Glucose uptake; NA; PTX; α1A-Adrenoceptor; Comp C; mTOR; AMPK; mTORC2; mTORC1; NRVM
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2017.11.016

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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 α1A-adrenoceptor (AR) couples to these protective pathways, and increased glucose uptake. We characterised α1A-AR signalling in CHO-K1 cells co-expressing the human α1A-AR and GLUT4 (CHOα1AGLUT4myc) and in neonatal rat ventricular cardiomyocytes (NRVM), and measured glucose uptake, intracellular Ca2+ mobilization, and phosphorylation of mTOR, Akt, 5′ adenosine monophosphate-activated kinase (AMPK) and S6 ribosomal protein (S6rp). In both systems, noradrenaline and the α1A-AR selective agonist A61603 stimulated glucose uptake by parallel pathways involving mTOR and AMPK, whereas another α1-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 CHOα1AGLUT4myc cells, siRNA directed against rictor but not raptor suppressed α1A-AR mediated glucose uptake. We have thus identified mTORC2 as a key component in glucose uptake stimulated by α1A-AR agonists. Our findings identify a novel link between the α1A-AR, mTORC2 and glucose uptake, that have been implicated separately in cardiomyocyte survival. Our studies provide an improved framework for examining the utility of α1A-AR selective agonists as tools in the treatment of cardiac dysfunction.