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P21‐activated kinase‐1 is necessary for depolarization‐mediated neuronal survival
Author(s) -
Johnson Kyle,
D'Mello Santosh R.
Publication year - 2005
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20415
Subject(s) - cdc42 , ly294002 , depolarization , protein kinase b , microbiology and biotechnology , cerebellum , neuroprotection , effector , biology , kinase , chemistry , rac1 , neuroscience , signal transduction , biophysics
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. © 2005 Wiley‐Liss, Inc.