Adrenaline increases glucose transport via a Rap1-p38MAPK pathway in rat vascular smooth muscle cells.
OBJECTIVE
Adrenaline has been implicated in the pathogenesis of atherosclerosis. However, little is known regarding the role of adrenaline in glucose transport in VSMC.


METHODS
In this study, we examined the effects of adrenaline on glucose uptake in rat VSMC. We also examined the downstream signaling pathway from the beta-adrenoceptor to glucose uptake, using a pharmacological approach. To investigate the downstream action of adenylate cyclase, we studied the effects of GGTI-298, an inhibitor of geranylgeranylation of GTPases, including Rap1. To confirm the involvement of Rap1, we silenced Rap1 by siRNA.


RESULTS
Adrenaline induced glucose uptake in a dose-dependent manner. The adrenaline-induced glucose uptake was inhibited by L-propranolol, (a selective beta-adrenoceptor antagonist), but not by prazosin (a selective alpha(1)-adrenoceptor antagonist) or UK14304 (a selective alpha(2)-adrenoceptor antagonist), suggesting the involvement of beta-adrenoceptors in glucose transport. Long-term treatment with cholera toxin, which resulted in sequestration of G(s) proteins, prevented the adrenaline-induced glucose uptake. Forskolin, a direct activator of adenylate cyclase, was found to mimic the effects of adrenaline. Adrenaline-induced glucose uptake was inhibited by GGTI-298, not by H89 (a selective inhibitor of PKA). Silencing of Rap1 by siRNA attenuated the adrenaline-induced glucose uptake. Adrenaline-induced glucose uptake was inhibited by SB203580 (a selective inhibitor of p38MAPK) and adrenaline-induced p38MAPK activation was inhibited by GGTI-298 and siRNA against Rap1.


CONCLUSIONS
These findings suggest that adrenaline-induced glucose transport is mediated by beta-adrenoceptors, G(s), adenylate cyclase, Rap1, and p38MAPK in vascular smooth muscle cells.
Kanda
Y
Y
Department of Pharmacology, National Defense Medical College, Tokorozawa, Saitama, Japan. kanda@ndmc.ac.jp
Watanabe
Y
Y
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D004837:Epinephrine / Q000494:pharmacology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*; D020827:rap1 GTP-Binding Proteins / Q000502:physiology*
D017868:Cyclic AMP-Dependent Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs; D020827:rap1 GTP-Binding Proteins; D005947:Glucose; D004837:Epinephrine