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_1A-Adrenoceptors Activate Glucose Uptake in L6 Muscle Cells through a Phospholipase C-, Phosphatidylinositol-3 Kinase-, and Atypical Protein Kinase C-Dependent Pathway

Department of Physiology, The Wenner-Gren Institute, Arrhenius Laboratories F3, Stockholm University, SE 10691 Stockholm, Sweden

Address all correspondence and requests for reprints to: Dr. Tore Bengtsson, Department of Physiology, The Wenner-Gren Institute, Arrhenius Laboratory F3, Stockholm University, SE 10691 Stockholm, Sweden. E-mail: tore.bengtsson{at}zoofys.su.se.

The role of ₁-adrenoceptor activation on glucose uptake in L6 cells was investigated. The ₁-adrenoceptor agonist phenylephrine [pEC₅₀ (–log₁₀ EC₅₀), 5.27 ± 0.30] or cirazoline (pEC₅₀, 5.00 ± 0.23) increased glucose uptake in a concentration-dependent manner, as did insulin (pEC₅₀, 7.16 ± 0.21). The ₂-adrenoceptor agonist clonidine was without any stimulatory effect on glucose uptake. The stimulatory effect of cirazoline was inhibited by the ₁-adrenoceptor antagonist prazosin, but not by the ß-adrenoceptor antagonist propranolol. RT-PCR showed that the _1A-adrenoceptor was the sole ₁-adrenoceptor subtype expressed in L6 cells. Cirazoline- or insulin-mediated glucose uptake was inhibited by the phosphatidylinositol-3 kinase inhibitor LY294002, suggesting a possible interaction between the ₁-adrenoceptor and insulin pathways. Cirazoline or insulin stimulated phosphatidylinositol-3 kinase activity, but ₁-adrenoceptor activation did not phosphorylate Akt. Both cirazoline- and insulin-mediated glucose uptake were inhibited by protein kinase C (PKC), phospholipase C, and p38 kinase inhibitors, but not by Erk1/2 inhibitors (despite both treatments being able to phosphorylate Erk1/2). Insulin and cirazoline were able to activate and phosphorylate p38 kinase. The phorbol ester 12-O-tetradecanoylphorbol-13-acetate and the calcium ionophore A23187 produced significant increases in glucose uptake, indicating roles for PKC and calcium in glucose uptake. Down-regulation of conventional PKC isoforms inhibited glucose uptake mediated by 12-O-tetradecanoylphorbol-13-acetate, but not by insulin or cirazoline. This study demonstrates that ₁-adrenoceptors mediate increases in glucose uptake in L6 muscle cells. This effect appears to be related to activation of phospholipase C, phosphatidylinositol-3 kinase, p38 kinase, and PKC.

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