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On the mechanism of cocaine inhibition of a membrane‐bound neurotransmitter receptor, the N ‐methyl‐D‐aspartate receptor
Author(s) -
Eagen Kyle P.,
Chen Yongli,
Lewis Ryan W.,
Hess George P.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a970-b
Subject(s) - chemistry , nmda receptor , receptor , nicotinic acetylcholine receptor , neurotransmitter , acetylcholine receptor , acetylcholine , neurotransmission , glutamate receptor , memantine , pharmacology , biophysics , channel blocker , neurotransmitter receptor , nicotinic agonist , biochemistry , biology , organic chemistry , calcium
Neurotransmitter receptors are members of a class of membrane‐bound proteins that play a major role in signal transmission between approximately 10 12 cells in the mammalian nervous system. Cocaine, a widely abused drug with a cost to society of more than 100 billion dollars a year, is a noncompetitive inhibitor of the nicotinic acetylcholine receptor (nAChR). Based on the inhibition mechanism, various small molecules were developed to prevent cocaine inhibition of the nAChR. Here we describe how cocaine inhibits the N ‐methyl‐D‐aspartate receptor (NMDAR). A newly developed flash‐lamp photolysis technique allows for kinetic investigations of neurotransmitter receptor mechanisms in the μs time region. Using this technique and expressing the NMDAR in transiently transfected HEK293 cells, we determined that cocaine binds with weak affinity (K I ~980 μM) to both the open‐ and closed‐channel receptor forms. These measurements further allowed us to determine the channel‐opening ( k op ) and ‐closing ( k cl ) rate constants, which give the channel‐opening equilibrium constant (Φ −1 = k op / k cl ). In a search for small molecules that prevent cocaine inhibition of the NMDAR, it was found that molecules that alleviate cocaine inhibition of the nAChR have either no effect on the NMDAR (ecgonine methyl ester, 3‐acetoxy ecgonine methyl ester, and RTI‐4229‐70) or inhibit it (ecgonine, K I ~1800 μM). Thus, cocaine inhibits the NMDAR by a different mechanism than it does the nAChR. Supported by an NIH grant NS08527 (G.P.H.) and a Robert J. Appel Cornell Presidential Research Scholarship (K.P.E.).