Arginase-NOS balance In the brain, arginase I and NOS are the primary enzymes that require arginine as a substrate, and both enzymes depend solely on arginine. Each of the three NOS isoforms (nNOS, eNOS and iNOS) make NO at varying levels while the arginase enzymes (Arg1 and Arg2) catalyze the production of ornithine. Ornithine is then utilized to form polyamines (and hence regulate cell proliferation via putrescine and spermidine or regulate NMDA channels via spermine). Ornithine is also utilized to form proline that in turn can be a starting point for synthesis of extracellular matrix proteins such as collagen. As a result, in cells that express both NOS and arginase I, NOS and arginase compete for arginine. When iNOS-mediated NO generation is high (bacterial infection, etc), arginase activity is usually low. However, NO production can be significantly lowered when arginase expression increases in the same cell. This is clearly seen in macrophages but we have shown the same phenomenon for nNOS in neurons (see below). Thus, the expression of arginase represents one powerful switch between pro-inflammatory stages and repair phases of neuroinflammation. Clearly, the supply of arginine can also impact these processes during inflammation.
Arginine is taken up by a series of specific membrane transporters termed cationic amino acid transporters (CATs) as well as by other transporters that are less arginine-specific. During inflammation, expression of one transporter, CAT2, is dramatically increased and provides the arginine required for the production of NO. We have studied the CAT transporters for a number of years and showed that arginine transport is dramatically increased in microglia of mice that express APOE4 compared to mice that only express APOE3. The increased arginine uptake is tightly linked to the global increase in the pro-inflammatory phase associated with APOE4. Because arginine is a critical amino acid for growth as well as for fighting infections, is the increased arginine uptake is also likely to mediate the beneficial effects of the APOE4 genotype in children with diarrhea.
- C. Colton, C. Brown, M. Czapiga and M. Vitek, Apolipoprotein E allele specific regulation of nitric oxide production, New York Acad. Sci., 962, 212-236, 2002.
- Czapiga, M. and Colton, C., Microglial function in human APOE3 and APOE4 transgenic mice: Altered arginine transport, J. Neuroimmunol. Jan; 134(1-2): 44-51, 2003.
- Bae, S.Y., Xu, Q., Hutchinson, D. Colton, C. Y+ and y+L arginine transporters in TH+ neuronal cell function Biochim Biophys Acta- Mol. Biol Disease,1745: 65-73,2005.
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