Abstract
Moderate hyperhomocysteinemia is associated with several diseases, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, and spina bifida. However, the mechanisms for their pathogenesis are unknown but could involve the interaction of homocysteine or its metabolites with molecular targets such as neurotransmitter receptors, channels, or transporters. We discovered that l-homocysteine sulfinic acid (l-HCSA),l-homocysteic acid, l-cysteine sulfinic acid, and l-cysteic acid are potent and effective agonists at several rat metabotropic glutamate receptors (mGluRs). These acidic homocysteine derivatives 1) stimulated phosphoinositide hydrolysis in the cells stably expressing the mGluR1, mGluR5, or mGluR8 (plus Gαqi9) and 2) inhibited the forskolin-induced cAMP accumulation in the cells stably expressing mGluR2, mGluR4, or mGluR6, with different potencies and efficacies depending on receptor subtypes. Of the four compounds, l-HCSA is the most potent agonist at mGluR1, mGluR2, mGluR4, mGluR5, mGluR6, and mGluR8. The effects of the four agonists were selective for mGluRs because activity was not discovered when l-HCSA and several other homocysteine derivatives were screened against a large panel of cloned neurotransmitter receptors, channels, and transporters. These findings imply that mGluRs are candidate G-protein-coupled receptors for mediating the intracellular signaling events induced by acidic homocysteine derivatives. The relevance of these findings for the role of mGluRs in the pathogenesis of homocysteine-mediated phenomena is discussed.
Footnotes
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↵1 This work was supported in part by the National Institute of Mental Health Psychoactive Drug Screening Program Grant MHN80002, Award KO2 MH01366 to B.L.R., Grant HL58982 to J.H.N., and Grant NS37436 to J.T.W.
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DOI: 10.1124/jpet.102.047092
- Abbreviations:
- HIOS
- homocysteine-induced oxidant stress
- l-HCSA
- l-homocysteine sulfinic acid
- d-HCSA
- d-homocysteine sulfinic acid
- l-HCA
- l-homocysteic acid
- d-HCA
- d-homocysteic acid
- dl-HCA
- dl-homocysteic acid
- l-CSA
- l-cysteine sulfinic acid
- l-CA
- l-cysteic acid
- mGluR
- metabotropic glutamate receptor
- dl-HCY
- dl-homocysteine
- l-CYS
- l-cysteine
- l-HCYT
- l-homocysteine thiolactone
- d-HCYT
- d-homocysteine thiolactone
- d-CTN
- d-cystine
- l-CTN
- l-cystine
- d-MET
- d-methionine
- l-MET
- l-methionine
- AP4
- 4-aminophosphonobutyrate
- l-GLU
- l-glutamate
- GR125,743
- N-[4-methoxy-3-(4-methyl piperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide
- HT
- hydroxytryptamine
- CHO
- Chinese hamster ovary
- IP
- inositol phosphate
- NMDA
- N-methyl-d-aspartate
- Aβ
- amyloid beta fragment
- PLC
- phospholipase C
- PI
- phosphoinositide
- PCP
- phencyclidine
- MK-801
- dizocilpine maleate
- Received November 18, 2002.
- Accepted December 19, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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