May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Caffeine: Effect on Glycine Receptors and Synaptic Transmission in Retina
Author Affiliations & Notes
  • L. Duan
    Dept of Neuroscience, State Univ of New York Buffalo, Buffalo, New York
  • M. M. Slaughter
    Dept of Neuroscience, State Univ of New York Buffalo, Buffalo, New York
  • Footnotes
    Commercial Relationships  L. Duan, None; M.M. Slaughter, None.
  • Footnotes
    Support  NEI Grant 14960
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 2433. doi:https://doi.org/
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    • Get Citation

      L. Duan, M. M. Slaughter; Caffeine: Effect on Glycine Receptors and Synaptic Transmission in Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2433. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Glycine receptors (GlyRs) shape synaptic responses of retinal ganglion cells. Strychnine is a potent antagonist but indiscriminative between GlyR subunits. We examined whether caffeine, a strychnine analog, would differentially inhibit GlyRs.

Methods: : Sybyl was used to compare caffeine and strychnine structures; AutoDock was used to dock antagonists to GlyRs obtained from homology modeling. Voltage-clamp recordings were performed in retinal slices of larval tiger salamanders or on GlyR cDNA transfected HEK cells. Drugs were applied by superfusion and light stimulation employed full field red (660nm) LEDs.

Results: : Both caffeine and strychinine can be aligned based on the presence of three electronegative atoms that may also act as hydrogen acceptors. Both antagonists can be docked to the same site at the interface made from two alpha3 GlyR subunits. The R159A mutation in α1 GlyR greatly decreases sensitivity to strychnine (Grudzinska et al, 2005), and similarly decreases sensitivity to caffeine. In retinal ganglion cells, caffeine inhibited 100 µM glycine activated currents with an IC50 of 1.65 mM. This inhibition was completely overcome by 5 mM glycine, suggesting a competitive antagonism. Other caffeine analogs also suppressed glycine currents. Using GlyR cDNA transfected HEK cells, the potency of caffeine varies with GlyR subtype: At equipotent glycine concentration (EC50), α1β GlyR was the least sensitive to caffeine suppression (IC50 of 837 µM) and most sensitive to glycine (EC50=60 µM); α3β was more sensitive to caffeine suppression (IC50 of 326 µM) while least sensitive to glycine (EC50=400 µM). Caffeine’s inhibition of GlyRs is not based on release of internal calcium or block of phosphodiesterase. On retinal ganglion cells, caffeine decreased the amplitude of both glycinergic sIPSCs and L-IPSCs, but did not change sIPSC frequency. Overall, the IC50 of caffeine on glycinergic L-IPSCs was approximately 1.65 mM. EPSCs were unaffected.

Conclusions: : Caffeine competitively inhibits GlyRs, most potently at α3β GlyR and least potently on α1β GlyR. Modeling and mutational studies suggest caffeine and strychnine interact with same amino acid residues on GlyR. Caffeine and glycine potencies in combination identify all GlyR subytpes.

Keywords: inhibitory receptors • retina: proximal (bipolar, amacrine, and ganglion cells) • electrophysiology: non-clinical 
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