AUTHOR=Nakamura Yukihiro TITLE=EGTA Can Inhibit Vesicular Release in the Nanodomain of Single Ca2+ Channels JOURNAL=Frontiers in Synaptic Neuroscience VOLUME=11 YEAR=2019 URL=https://www.frontiersin.org/journals/synaptic-neuroscience/articles/10.3389/fnsyn.2019.00026 DOI=10.3389/fnsyn.2019.00026 ISSN=1663-3563 ABSTRACT=

The exogenous Ca2+ chelator EGTA (ethylene glycol tetraacetic acid) has been widely used to probe the coupling distance between Ca2+ channels and vesicular Ca2+ sensors for neurotransmitter release. Because of its slow forward rate for binding, EGTA is thought to not capture calcium ions in very proximity to a channel, whereas it does capture calcium ions at the remote distance. However, in this study, our reaction diffusion simulations (RDSs) of Ca2+ combined with a release calculation using vesicular sensor models indicate that a high concentration of EGTA decreases Ca2+ and vesicular release in the nanodomain of single channels. We found that a key determinant of the effect of EGTA on neurotransmitter release is the saturation of the vesicular sensor. When the sensor is saturated, the reduction in the Ca2+ concentration by EGTA is masked. By contrast, when the sensor is in a linear range, even a small reduction in Ca2+ by EGTA can decrease vesicular release. In proximity to a channel, the vesicular sensor is often saturated for a long voltage step, but not for a brief Ca2+ influx typically evoked by an action potential. Therefore, when EGTA is used as a diagnostic tool to probe the coupling distance, care must be taken regarding the presynaptic Ca2+ entry duration as well as the property of the vesicular Ca2+ sensor.