p21-Activated kinase-1 is necessary for depolarization-mediated neuronal survival.
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.
Johnson
Kyle
K
Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX 75083, USA.
D'Mello
Santosh R
SR
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
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