Background Caffeine stimulates calcium-induced calcium release (CICR) in many cell types. In neurons, caffeine stimulates CICR presynaptically and thus modulates neurotransmitter release. Methodology/Principal Findings 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/Significance 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.
References
[1]
Ehrlich BE, Kaftan E, Bezprozvannaya S, Bezprozvanny I (1994) The pharmacology of intracellular Ca2+-release channels. Trends Pharmacological Sci 15:
[2]
Rousseau E, LaDine J, Liu Q, Meissner G (1988) Activation of the Ca2+ release channel of skeletal muscle sarcoplasmic reticulum by caffeine and related compounds. Archives of Biochemistry and Biophysics 267: 75–86.
[3]
Bezprozvanny I, Bezprozvannaya S, Ehrlich BE (1994) Caffeine-induced inhibition of Inositol(1,4,5)-Trisphosphate-gated Calcium Channels from Cerebellum. Molecular Biology of the Cell 5: 97–103.
[4]
Sharma G, Vijayaraghavan S (2003) Modulation of presynaptic store calcium induces release of glutamate and postsynaptic firing. Neuron 38: 929–939.
[5]
Martin ED, Buno W (2003) Caffeine-mediated presynaptic long-term potentiation in hippocampal CA1 pyramidal neurons. Journal of Neurophysiology 89: 3029–3038.
[6]
Morton-Jones RT, Cannell MB, Housley GD (2007) Ca2+ entry via AMPA-type glutamate receptors triggers Ca2+-induced Ca2+ release from ryanodine receptors in rat spiral ganglion neurons. Cell Calcium 43: 356–366.
[7]
Edwards RH (2007) The neurotransmitter cycle and quantal size. Neuron 55: 835–858.
[8]
Wu X, Xue L, Mohan R, Paradiso K, Gillis K, et al. (2007) The origin of quantal size variation: vesicular glutamate concentration plays a significant role. The Journal of Neuroscience 27: 3046–3056.
[9]
Ashby MC, De La Rue SA, Ralph GS, Uney J, Collingridge GL, et al. (2004) Removal of AMPA receptors (AMPARs) from synapses is preceded by transient endocytosis of extrasynaptic AMPARs. The Journal of Neuroscience 24: 5172–5176.
[10]
Simkus CRL, Stricker C (2002) The contribution of intracellular calcium stores to mEPSCs recorded in layer II neurones of rat barrel cortex. Journal of Physiology 545: 521–535.
[11]
Swanson GT, Kamboj SK, Cull-Candy SG (1997) Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. J Neurosci 17: 58–69.
[12]
Cysneiros RM, Farkas D, Harmatz JS, von Moltke LL, Greenblatt DJ (2007) Pharmacokinetic and pharmacodynamic interactions between Zolpidem and caffeine. Nature Clinical Pharmacology and Therapeutics 82: 54–62.
[13]
Liu X, Smith BJ, Chen C, Callegari E, SBecker SL, et al. (2006) Evaluation of cerebrospinal fluid concentration and plasma free concentration as a surrogate measurement for brain free concentration. Drug Metabolism and Disposition 34: 1443–1447.
[14]
Daly JW, Butts-Lamb P, Padgett W (1983) Subclasses of adenosine receptors in the central nervous system: Interaction with caffeine and related methylxanthines. Cellular and Molecular Neurobiology 3: 69–80.
[15]
Gundlfinger A, Bischofberger J, Johenning FW, Torvinen M, Schmitz D, et al. (2007) Adenosine modulates transmission at the hippocampal mossy fibre synapse via direct inhibition of presynaptic calcium channels. Journal of Physiology 582: 263–277.
[16]
Mrvos RM, Reilly PE, Dean BS, Krenzelok EP (1989) Massive caffeine ingestion resulting in death. Vet Hum Toxicol 6: 571–572.
[17]
Traynelis SF (1998) Software-based correction of single compartment series resistance errors. Journal of Neuroscience Methods 86: 25–34.
