Fast inhibition of glutamate-activated currents by caffeine.
BACKGROUND
Caffeine stimulates calcium-induced calcium release (CICR) in many cell types. In neurons, caffeine stimulates CICR presynaptically and thus modulates neurotransmitter release.


RESULTS
Using the whole-cell patch-clamp technique we found that caffeine (20 mM) reversibly increased the frequency and decreased the amplitude of miniature excitatory postsynaptic currents (mEPSCs) in neocortical neurons. The increase in mEPSC frequency is consistent with a presynaptic mechanism. Caffeine also reduced exogenously applied glutamate-activated currents, confirming a separate postsynaptic action. This inhibition developed in tens of milliseconds, consistent with block of channel currents. Caffeine (20 mM) did not reduce currents activated by exogenous NMDA, indicating that caffeine block is specific to non-NMDA type glutamate receptors.


CONCLUSIONS
Caffeine-induced inhibition of mEPSC amplitude occurs through postsynaptic block of non-NMDA type ionotropic glutamate receptors. Caffeine thus has both pre and postsynaptic sites of action at excitatory synapses.
Vyleta
Nicholas P
NP
Division of Pulmonary & Critical Care Medicine, Oregon Health & Science University, Portland, Oregon, USA.
Smith
Stephen M
SM
D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008954:Models, Biological; D016202:N-Methylaspartate / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D015220:Calcium Channels; D000697:Central Nervous System Stimulants; D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D002110:Caffeine; D018698:Glutamic Acid; D016202:N-Methylaspartate; D002118:Calcium
Cell Mol Neurobiol. 1983 Mar;3(1):69-80
6309393
Neuron. 2003 Jun 19;38(6):929-39
12818178
Arch Biochem Biophys. 1988 Nov 15;267(1):75-86
2848455
Trends Pharmacol Sci. 1994 May;15(5):145-9
7754532
Drug Metab Dispos. 2006 Sep;34(9):1443-7
16760229
Neuron. 2007 Sep 20;55(6):835-58
17880890
J Neurophysiol. 2003 Jun;89(6):3029-38
12783948
J Physiol. 2002 Dec 1;545(2):521-35
12456831
Cell Calcium. 2008 Apr;43(4):356-66
17719086
Vet Hum Toxicol. 1989 Dec;31(6):571-2
2617841
J Neurosci. 2007 Mar 14;27(11):3046-56
17360928
J Neurosci. 1997 Jan 1;17(1):58-69
8987736
J Neurosci. 2004 Jun 2;24(22):5172-6
15175386
Mol Biol Cell. 1994 Jan;5(1):97-103
8186468
Clin Pharmacol Ther. 2007 Jul;82(1):54-62
17443132
J Neurosci Methods. 1998 Dec 31;86(1):25-34
9894783
J Physiol. 2007 Jul 1;582(Pt 1):263-77
17478533