Trophic agents that prevent neuronal apoptosis activate calpain and down-regulate CaMKIV.
CaMKIV is enriched in neuronal nuclei and mediates Ca2+-dependent survival via transcription factor phosphorylation. Cultured cerebellar granule neurons were used to examine whether distinct modes of Ca2+ signaling differentially modulate CaMKIV expression and function. For long-term survival, these neurons require 25 mm KCl or NMDA, which stimulates Ca2+ entry through voltage-sensitive Ca2+ channels or NMDA receptors (NRs). Lower levels of Ca2+ entry through NRs support survival of a neuronal subpopulation grown in 5 mm KCl media. Several effects were demonstrated: (i) sustained exposure to 25 mM KCl or 140 microM NMDA produced CaMKIV down-regulation, compared to 5 mM KCl cultures; (ii) CaMKIV down-regulation was attenuated by nifedipine, APV and CaM kinase inhibitors, indicating that it is Ca2+ dependent and reversible; (iii) down-regulation was both selective for nuclear substrates and calpain-mediated; (iv) proteolysis was exacerbated by leptomycin B, a nuclear export inhibitor. Although CaMKIV proteolysis by trophic agents seems paradoxical in light of evidence supporting its critical role in survival, the CaMKIV/CREB signal transduction pathway was preserved, as assessed by CaM kinase-mediated CREB phosphorylation, and the ability of CaM kinase inhibitors to interfere with KCl-mediated survival. We hypothesize that limited calpain-mediated proteolysis of CaMKIV is a negative feedback response to the sustained activation of a Ca2+ and CaMKIV signaling pathway by these agents.
Tremper-Wells
Barbara
B
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York 13210, USA.
Mathur
Anjili
A
Beaman-Hall
Carol M
CM
Vallano
Mary Lou
ML
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D028884:Karyopherins / Q000037:antagonists & inhibitors; D016202:N-Methylaspartate / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein
D000903:Antibiotics, Antineoplastic; D002118:Calcium; D002121:Calcium Channel Blockers; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002154:Calpain; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D028884:Karyopherins; D016202:N-Methylaspartate; D011189:Potassium Chloride; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C517686:Camk4 protein, rat; C038753:leptomycin B