Ophthalmology Research
Sorting and Expression of GAP-43 in the Retina
GAP-43 is an intracellular protein that allows neurons to follow extracellular signals. These signals direct the neurons to their proper destination during development and following injury. When the optic nerve is transected close to retinal ganglion cell bodies, GAP-43 is up-regulated as in peripheral nerves, and axonal regrowth occurs.
It is not known why the protein is not up-regulated at more distal transection sites in the optic nerve or in other central neurons. The latter effect may be due to a problem in up-regulation of GAP-43 gene expression or in the sorting and transport of GAP-43 from the cell body to the site of injury. In the normal adult retina, GAP-43 is expressed essentially in only one cell type, the dopaminergic amacrine cell, and may be involved in controlling the release of dopamine from terminals of this cell located in the inner plexiform layer. GAP-43 is also present in the sensory nerve terminals of the normal cornea, and may participate in their remodeling.
All of the effects of the protein appear to derive from the interaction of its positively charged effector domain, located in the N-terminal half of the molecule, with (1) calmodulin, (2) the negatively charged membrane phospholipid phosphatidylinositol (4,5) bisphosphate, and (3) cortical actin filaments that are located just under the plasma membrane, in a sequence which depends on the activation level of the neuron at a particular moment. We have shown that nonubiquitinated GAP-43 is attacked by the proteasome, which is a large proteinase complex located in the cytosol of cells. GAP-43 is unusual in being primarily unfolded in its native state. This appears to allow the proteasome attack, which could limit GAP-43 expression. Palmitoylation is necessary for GAP-43 to become membrane associated and sorted to its correct destination. We have shown that GAP-43 is palmitoylated by the endoplasmic reticulum — Golgi. The technique of cell-free translation of GAP-43 mRNA in reticulocyte lysate is used because the sorting and interactions of GAP-43 can be observed immediately after exit of the protein from the ribosome. We would like to further examine the role of palmitoylation in the sorting and expression of GAP-43, and to determine how this contributes to the function of the protein both in the normal retina and in optic nerve regeneration.
Reference: Denny, J.B. (2004) Growth-associated protein of 43kDa (GAP-43) is cleaved nonprocessively by the 20S proteasome. Eur. J. Biochem, 271,2480 - 2493.
Contact Person: John B. Denny, Ph.D.
UTHSCSA, Department of Ophthalmology, MC-6230
7703 Floyd Curl Drive
San Antonio, TX 78229-3900
(210) 567-8439
FAX (210) 567-8413
Email: denny@uthscsa.edu
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© 1996-2005 UTHSCSA Department of Ophthalmology
Updated 10 Nov 2005