Caffeine inhibition of ionotropic glycine receptors

Center for Neuroscience, 124 Sherman Hall, University at Buffalo, Buffalo, NY 14214, USA.
The Journal of Physiology (Impact Factor: 5.04). 07/2009; 587(Pt 16):4063-75. DOI: 10.1113/jphysiol.2009.174797
Source: PubMed


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: alpha2beta (248 +/- 32 microm) alpha3beta (255 +/- 16 microm) > alpha4beta (517 +/- 50 microm) > alpha1beta(837 +/- 132 microm). However, because the alpha3beta 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 alpha1beta 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.

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    • "It is widely used as a psychoactive stimulant [2] because it has the ability to interact with neurotransmission and induces a release of excitatory neurotransmitters while blocking adenosine receptors [3]. In addition, caffeine is a structural analogue of strychnine [4]. It competitively binds and antagonizes the glycine receptor. "
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