CaMKII and CaMKIV mediate distinct prosurvival signaling pathways in response to depolarization in neurons.
By fusing the CaMKII-inhibitory peptide AIP to GFP, we constructed a specific and effective CaMKII inhibitor, GFP-AIP. Expression of GFP-AIP and/or dominant-inhibitory CaMKIV in cultured neonatal rat spiral ganglion neurons (SGNs) shows that CaMKII and CaMKIV act additively and in parallel to mediate the prosurvival effect of depolarization. Depolarization or expression of constitutively active CaMKII functionally inactivates Bad, indicating that this is one means by which CaMKII promotes neuronal survival. CaMKIV, but not CaMKII, requires CREB to promote SGN survival, consistent with the exclusively nuclear localization of CaMKIV and indicating that the principal prosurvival function of CaMKIV is activation of CREB. Consistent with this, a constitutively active CREB construct that provides a high level of CREB activity promotes SGN survival, although low levels of CREB activity did not do so. Also, in apoptotic SGNs, activation of CREB by depolarization is disabled, presumably as part of a cellular commitment to apoptosis.
Bok
Jinwoong
J
Department of Biological Sciences, University of Iowa, Iowa City, IA 52242, USA.
Wang
Qiong
Q
Huang
Jie
J
Green
Steven H
SH
D000818:Animals; D000831:Animals, Newborn; D050882:CREB-Binding Protein / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000502:physiology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D010455:Peptides / Q000378:metabolism; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D013136:Spiral Ganglion / Q000166:cytology; D014162:Transfection; D051025:bcl-Associated Death Protein / Q000378:metabolism
C494821:Bad protein, rat; C503464:CaMKII inhibitor AIP; D016900:Neurofilament Proteins; D010455:Peptides; D051025:bcl-Associated Death Protein; C051774:neurofilament protein H; D049452:Green Fluorescent Proteins; D011189:Potassium Chloride; D050882:CREB-Binding Protein; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; C517686:Camk4 protein, rat