Janus kinase 2, an early target of alpha 7 nicotinic acetylcholine receptor-mediated neuroprotection against Abeta-(1-42) amyloid.
The molecular mechanisms of alpha7 nicotinic acetylcholine receptor (nAChR)-mediated neuroprotection remain unclear. In this study we provide evidence that nicotine stimulation of alpha7 nAChR transduces signals to phosphatidylinositol 3-kinase and Akt via Janus kinase 2 (JAK2) in a cascade, which results in neuroprotection. Exposure to beta-amyloid results in the activation of the apoptotic enzyme caspase-3 and cleavage of the DNA-repairing enzyme poly-(ADP-ribose) polymerase. This cascade is inhibited by nicotine through JAK2 activation, and these effects are blocked by preincubation with the JAK2-specific inhibitor AG-490. We also found that pretreatment of cells with angiotensin II blocks the nicotine-induced activation of JAK2 via the AT(2) receptor and completely prevents alpha7 nAChR-mediated neuroprotective effects further suggesting a pivotal role for JAK2. These findings identify novel mechanisms of receptor interactions relevant to neuronal viability and suggest novel therapeutic strategies to optimize neuroprotection.
Shaw
Seán
S
Vascular Biology Center, Medical College of Georgia, Augusta, Georgia 30912-2500, USA.
Bencherif
Merouane
M
Marrero
Mario B
MB
D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002038:Bungarotoxins / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D053614:Janus Kinase 2; D018696:Neuroprotective Agents / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D016716:PC12 Cells / Q000187:drug effects*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; D000804:Angiotensin II; D057911:Angiotensin Receptor Antagonists; D002038:Bungarotoxins; D053148:Caspase 3; D020169:Caspases; D004791:Enzyme Inhibitors; D053614:Janus Kinase 2; D018696:Neuroprotective Agents; D009538:Nicotine; D018722:Nicotinic Agonists; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011978:Receptors, Nicotinic; D012694:Serine; D014443:Tyrosine; D020032:Tyrphostins; D064569:alpha7 Nicotinic Acetylcholine Receptor; C579167:Chrna7 protein, human; C579165:Chrna7 protein, rat; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C075222:amyloid beta-protein (1-42); C499320:PARP1 protein, human; C499322:Parp1 protein, rat; C507924:JAK2 protein, human; C507927:Jak2 protein, rat; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; C505407:CASP3 protein, human; C505410:Casp3 protein, rat