title: The neuroprotective effect of 2-(3-pyridyl)-1-azabicyclo[3.2.2]nonane (TC-1698), a novel alpha7 ligand, is prevented through angiotensin II activation of a tyrosine phosphatase.
abstract: We have recently provided evidence for nicotine-induced complex formation between the alpha7 nicotinic acetylcholine receptor (nAChR) and the tyrosine-phosphorylated enzyme Janus kinase 2 (JAK2) that results in subsequent activation of phosphatidylinositol-3-kinase (PI-3-K) and Akt. Nicotine interaction with the alpha7 nAChR inhibits Abeta (1-42) interaction with the same receptor, and the Abeta (1-42)-induced apoptosis is prevented through nicotine-induced activation of JAK2. These effects can be shown by measuring markers of cytotoxicity, including the cleavage of the nuclear protein poly(ADP-ribose) polymerase (PARP), the induction of caspase 3, or cell viability. In this study, we found that 2-(3-pyridyl)-1-azabicyclo[3.2.2]nonane (TC-1698), a novel alpha7-selective agonist, exerts neuroprotective effects via activation of the JAK2/PI-3K cascade, which can be neutralized through activation of the angiotensin II (Ang II) AT(2) receptor. Vanadate not only augmented the TC-1698-induced tyrosine phosphorylation of JAK2 but also blocked the Ang II neutralization of TC-1698-induced neuroprotection against Abeta (1-42)-induced cleavage of PARP. Furthermore, when SHP-1 was neutralized via antisense transfection, the Ang II inhibition of TC-1698-induced neuroprotection against Abeta (1-42) was prevented. These results support the main hypothesis that states that JAK2 plays a central role in the nicotinic alpha7 receptor-induced activation of the JAK2-PI-3K cascade in PC12 cells, which ultimately contribute to nAChR-mediated neuroprotection. Ang II inhibits this pathway through the AT(2) receptor activation of the protein tyrosine phosphatase SHP-1. This study supports central and opposite roles for JAK2 and SHP-1 in the control of apoptosis and alpha7-mediated neuroprotection in PC12 cells.
authors.affiliation: Targacept Inc., 200 East First Street, Suite 300, Winston-Salem, NC 27101-4165, USA.
authors.forename: Mario B
authors.initials: MB
authors.lastname: Marrero
authors.forename: Roger L
authors.initials: RL
authors.lastname: Papke
authors.forename: Balwinder S
authors.initials: BS
authors.lastname: Bhatti
authors.forename: Seán
authors.initials: S
authors.lastname: Shaw
authors.forename: Merouane
authors.initials: M
authors.lastname: Bencherif
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology*; D029721:Drosophila Proteins; D004789:Enzyme Activation; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D000804:Angiotensin II; D001643:Bridged Bicyclo Compounds; D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011978:Receptors, Nicotinic; D012694:Serine; D014443:Tyrosine; D020032:Tyrphostins; D064569:alpha7 Nicotinic Acetylcholine Receptor; C484276:2-(3-pyridyl)-1-azabicyclo(3.2.2)nonane; C579165:Chrna7 protein, rat; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C113681:nicotinic acetylcholine receptor alpha-subunits, Drosophila; C507927:Jak2 protein, rat; C494920:Akt1 protein, rat; C509250:Ptpn6 protein, rat