title: p21-Activated kinase-1 is necessary for depolarization-mediated neuronal survival.
abstract: Cerebellar granule neurons undergo apoptosis when switched from culture medium containing high potassium (HK) to medium that contains low potassium (LK). HK treatment leads to an activation of p21-activated kinase-1 (PAK-1). Overexpression of a constitutively active form of PAK-1 protects against apoptosis in LK medium. Overexpression of a dominant-negative form of PAK-1 blocks survival in HK. Although PAK-1 is usually considered to be a downstream effector of Rac and Cdc42, we were unable to detect association between PAK-1 and either Rac1 or Cdc42 in cerebellar granule neurons. Interaction between PAK-1 and PDK1 is detected in granule neurons, although there is no change in the extent of interaction in neurons primed to die. Neuronal survival by PAK-1 overexpression is not inhibited by PD98059 or LY294002, which inhibit the activity of MEK and PI-3 kinase, respectively. The ability of PAK-1 to maintain neuronal survival is, however, blocked by ML-9, a compound known to inhibit Akt. Our results show that that PAK-1 is necessary for neuronal survival in HK and suggest that its neuroprotective action may be mediated by a GTPase-independent, but Akt-dependent, mechanism.
authors.affiliation: Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75083, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Johnson
authors.forename: Santosh R
authors.initials: SR
authors.lastname: D'Mello
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D047468:Immunoprecipitation / Q000379:methods; D007211:Indoles / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D013997:Time Factors; D014162:Transfection / Q000379:methods; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D007211:Indoles; C007293:DAPI; D007334:Insulin-Like Growth Factor I; D064413:3-Phosphoinositide-Dependent Protein Kinases; C515906:Pak1 protein, rat; C515910:Pak2 protein, rat; C578579:Pdpk1 protein, rat; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D011188:Potassium