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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1
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pubmed:dateCreated |
2004-3-29
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pubmed:abstractText |
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.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Akt1 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Angiotensin II,
http://linkedlifedata.com/resource/pubmed/chemical/Bicyclo Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Drosophila Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Intracellular Signaling Peptides...,
http://linkedlifedata.com/resource/pubmed/chemical/Jak2 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Janus Kinase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Neuroprotective Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphatidylinositol 3-Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatase...,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Tyrosine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Ptpn6 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Nicotinic,
http://linkedlifedata.com/resource/pubmed/chemical/Serine,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/Tyrphostins,
http://linkedlifedata.com/resource/pubmed/chemical/alpha-cyano-(3,4-dihydroxy)-N-benzyl...,
http://linkedlifedata.com/resource/pubmed/chemical/alpha7 nicotinic acetylcholine...,
http://linkedlifedata.com/resource/pubmed/chemical/nicotinic acetylcholine receptor...
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0022-3565
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
309
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
16-27
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:14722323-Angiotensin II,
pubmed-meshheading:14722323-Animals,
pubmed-meshheading:14722323-Apoptosis,
pubmed-meshheading:14722323-Bicyclo Compounds,
pubmed-meshheading:14722323-Drosophila Proteins,
pubmed-meshheading:14722323-Enzyme Activation,
pubmed-meshheading:14722323-Intracellular Signaling Peptides and Proteins,
pubmed-meshheading:14722323-Janus Kinase 2,
pubmed-meshheading:14722323-Neuroprotective Agents,
pubmed-meshheading:14722323-PC12 Cells,
pubmed-meshheading:14722323-Phosphatidylinositol 3-Kinases,
pubmed-meshheading:14722323-Phosphorylation,
pubmed-meshheading:14722323-Protein Tyrosine Phosphatase, Non-Receptor Type 6,
pubmed-meshheading:14722323-Protein Tyrosine Phosphatases,
pubmed-meshheading:14722323-Protein-Serine-Threonine Kinases,
pubmed-meshheading:14722323-Protein-Tyrosine Kinases,
pubmed-meshheading:14722323-Proto-Oncogene Proteins,
pubmed-meshheading:14722323-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:14722323-Pyridines,
pubmed-meshheading:14722323-Rats,
pubmed-meshheading:14722323-Receptors, Nicotinic,
pubmed-meshheading:14722323-Serine,
pubmed-meshheading:14722323-Tyrosine,
pubmed-meshheading:14722323-Tyrphostins
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pubmed:year |
2004
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pubmed:articleTitle |
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.
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pubmed:affiliation |
Targacept Inc., 200 East First Street, Suite 300, Winston-Salem, NC 27101-4165, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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