Physiological and pathological caspase cleavage of the neuronal RasGEF GRASP-1 as detected using a cleavage site-specific antibody

Neuroscience. 2002;114(1):217-27. doi: 10.1016/s0306-4522(02)00142-2.


Caspases are proteases involved in various physiological and pathological processes in the nervous system, including development and pathogenesis. GRASP-1 is a recently identified neuronal substrate of caspase-3-subfamily caspases. It is a Ras-guanine nucleotide exchange factor (RasGEF) that interacts with the glutamate receptor interacting protein (GRIP). This alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor/GRIP protein complex has been proposed to be involved in AMPA receptor synaptic targeting. The caspase-3 cleavage of GRASP-1 separates the N-terminal RasGEF catalytic domain from the C-terminal GRIP-interacting region, potentially disrupting regulation of the RasGEF activity by GRIP. To examine the regulation and regional distribution of the caspase-3 cleavage of GRASP-1 in vivo, we generated a cleavage site-specific antibody, termed CGP, against the cleaved N-terminal fragment of GRASP-1. Using this antibody, we have examined the caspase cleavage of GRASP-1 during postnatal development and following ischemia in mice. We found that caspase cleavage of GRASP-1 occurs in specific brain regions in a time-dependent manner during development and ischemia. This data provides an important account of the brain areas that might require caspase-3 activity in postnatal development and ischemic damage, which has not been documented. It also demonstrates that the CGP antibody is a powerful tool for studying neuronal activity of the caspase-3-subfamily caspases in vivo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Animals, Newborn
  • Antibody Specificity / immunology
  • Brain / cytology
  • Brain / growth & development
  • Brain / metabolism*
  • Brain Ischemia / metabolism
  • Brain Ischemia / physiopathology
  • Carrier Proteins / metabolism*
  • Caspase 3
  • Caspases / metabolism*
  • Catalytic Domain / physiology
  • Cell Death / physiology
  • Cells, Cultured
  • Functional Laterality / physiology
  • Immunohistochemistry
  • Infarction, Middle Cerebral Artery / metabolism
  • Infarction, Middle Cerebral Artery / physiopathology
  • Membrane Proteins
  • Mice
  • Neostriatum / metabolism
  • Neostriatum / physiopathology
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Protein Structure, Tertiary / physiology
  • Receptors, AMPA / metabolism*
  • ras Guanine Nucleotide Exchange Factors / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Grip1 protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Receptors, AMPA
  • ras Guanine Nucleotide Exchange Factors
  • tamalin protein, human
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases