Calcineurin-mediated BAD dephosphorylation activates the caspase-3 apoptotic cascade in traumatic spinal cord injury.
We report here that activation of the caspase-3 apoptotic cascade in spinal cord injury is regulated, in part, by calcineurin-mediated BAD dephosphorylation. BAD, a proapoptotic member of the bcl-2 gene family, is rapidly dephosphorylated after injury, dissociates from 14-3-3 in the cytosol, and translocates to the mitochondria of neurons where it binds to Bcl-x(L). Pretreatment of animals with FK506, a potent inhibitor of calcineurin activity, or MK801, an NMDA glutamate receptor antagonist, blocked BAD dephosphorylation and abolished activation of the caspase-3 apoptotic cascade. These findings extend previous in vitro observations and are the first to implicate the involvement of glutamate-mediated calcineurin activation and BAD dephosphorylation as upstream, premitochondrial signaling events leading to caspase-3 activation in traumatic spinal cord injury.
Springer
J E
JE
Department of Anatomy and Neurobiology, University of Kentucky Medical Center, Center for Spinal Cord and Brain Injury Research, Lexington, Kentucky 40536-0084, USA.jspring@pop.uky.edu
Azbill
R D
RD
Nottingham
S A
SA
Kennedy
S E
SE
D048948:14-3-3 Proteins; D000818:Animals; D017209:Apoptosis; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003288:Contusions / Q000378:metabolism*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D015151:Immunoblotting; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013119:Spinal Cord Injuries / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein
D048948:14-3-3 Proteins; C494821:Bad protein, rat; C494813:Bcl2l1 protein, rat; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; D007166:Immunosuppressive Agents; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D016291:Dizocilpine Maleate; D014446:Tyrosine 3-Monooxygenase; D019703:Calcineurin; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D016559:Tacrolimus