Adrenaline increases glucose transport via a Rap1-p38MAPK pathway in rat vascular smooth muscle cells

Kanda Y, Watanabe Y
Source: Br J Pharmacol
Publication Date: (2007)
Issue: 151(4): 476-82
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Aortic Smooth Muscle Cells (R-ASM), Rat
Species: rat
Tissue Origin: aortic
Nucleofector® I/II/2b
Background and purpose:Adrenaline has been implicated in the pathogenesis of atherosclerosis. However, little is known regarding the role of adrenaline in glucose transport in VSMC.Experimental approach: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.Key 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 and implications: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.