G protein and cAMP-dependent protein kinase mediate amyloid beta-peptide inhibition of neuronal glucose uptake.
The mechanism by which amyloid beta-peptide (Abeta) inhibits glucose uptake in cultured cells is not known. Here we demonstrated a signaling pathway in which Abeta25-35, a neurotoxic portion of the Abeta peptide corresponding to amino acids 25-35, inhibits neuronal glucose uptake by hippocampal neurons. The GP antagonist-2, which blocks Gs, prevented the inhibitory effect of Abeta on the glucose uptake. Exposure of cells to Abeta resulted in a transitory increase in intracellular levels of cAMP. To assess the role of cAMP in neuronal glucose uptake, cultured neurons were exposed to dibutyryl cAMP (Bt2cAMP) or an adenylyl cyclase activator, forskolin. Both Bt2cAMP and forskolin inhibited neuronal glucose uptake, and cAMP-dependent protein kinase (PKA) inhibitor KT5720 blocked the Abeta-mediated inhibition of glucose uptake. Cholera toxin, which stimulates adenylyl cyclase by activating Gs protein, also inhibited neuronal glucose uptake, and Abeta potentiated this inhibitory effect of cholera toxin on glucose uptake. Thus, our findings suggest that Abeta inhibits glucose uptake by activating the Gs-coupled receptors and involves the cAMP-PKA system.
Prapong
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Department of Biomedical Sciences, Iowa State University, 2008 Veterinary Medicine Building, Ames, Iowa 50011, USA.
Uemura
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Hsu
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D000262:Adenylyl Cyclases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002227:Carbazoles; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005947:Glucose / Q000493:pharmacokinetics*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D002227:Carbazoles; D004791:Enzyme Inhibitors; D007211:Indoles; D010446:Peptide Fragments; D011758:Pyrroles; C074636:amyloid beta-protein (25-35); D005576:Colforsin; C057416:KT 5720; D003994:Bucladesine; D002772:Cholera Toxin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D005947:Glucose