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Caffeine inhibition of ionotropic glycine receptors
Author(s) -
Duan Lei,
Yang Jaeyoung,
Slaughter Malcolm M.
Publication year - 2009
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2009.174797
Subject(s) - glycine receptor , strychnine , ionotropic effect , caffeine , chemistry , glycine , inhibitory postsynaptic potential , pharmacology , receptor , biochemistry , biology , nmda receptor , neuroscience , endocrinology , amino acid
We found that caffeine is a structural analogue of strychnine and a competitive antagonist at ionotropic glycine receptors (GlyRs). Docking simulations indicate that caffeine and strychnine may bind to similar sites at the GlyR. The R131A GlyR mutation, which reduces strychnine antagonism without suppressing activation by glycine, also reduces caffeine antagonism. GlyR subtypes have differing caffeine sensitivity. Tested against the EC 50 of each GlyR subtype, the order of caffeine potency (IC 50 ) is: α2β (248 ± 32 μ m ) ≈α3β (255 ± 16 μ m ) > α4β (517 ± 50 μ m ) > α1β(837 ± 132 μ m ). However, because the α3β GlyR is more than 3‐fold less sensitive to glycine than any of the other GlyR subtypes, this receptor is most effectively blocked by caffeine. The glycine dose–response curves and the effects of caffeine indicate that amphibian retinal ganglion cells do not express a plethora of GlyR subtypes and are dominated by the α1β GlyR. Comparing the effects of caffeine on glycinergic spontaneous and evoked IPSCs indicates that evoked release elevates the glycine concentration at some synapses whereas summation elicits evoked IPSCs at other synapses. Caffeine serves to identify the pharmacophore of strychnine and produces near‐complete inhibition of glycine receptors at concentrations commonly employed to stimulate ryanodine receptors.