Kissing or Fused Since Some Time

I am particularly interested in the data published by Brown et al. (2010) in their paper entitled " Vesicular release of gluta-mate utilizes the proton gradient between the vesicle and the synaptic cleft ". The paper presents a decrease in transmitter output when the extracellular pH is acidified. The authors interpret their observation in terms of interference with the pH gradient from the vesicular lumen and the bulk extracel-lular medium when the vesicles are assumed to be " kissing " , which is when vesicles are believed to open to the extracellular milieu without completely fusing with the presy-naptic plasma membrane. However, vesic-ular kisses have been seriously challenged (Chen et al., 2008; Granseth et al., 2009) and another interpretation may be drawn from the data. Exocytosis was originally proposed to support the brevity of presynaptic transmitter output that account for postsynap-tic transient responses. Indeed fast freezing electron microscopy and membrane labeling techniques demonstrated that exo-cytosis is involved in presynaptic activity, hence, the opening of the vesicular lumen is now automatically assumed to be the mechanism that releases the transmitter. However, membrane labeling techniques fail to show as many vesicular fusions than there are elementary transmission recorded. Consequently it is commonly assumed that the pore may also open only transiently without the vesicle fusing according to the " kiss-and-run " hypothesis. This assumption , although challenged at fast synapses (Chen et al., 2008; Granseth et al., 2009), is imposed by the conviction that the sole possible release mechanism is the opening of the fusion pore. Paradoxically, the authors also recognized " that diffusion of [the transmitter] glutamate through the pore would be too slow to generate the rapid rise in glutamate in the cleft to produce the time-course of synaptic currents. " This means that the opening of the pore is still thought to occur but not sufficient for fast release. The authors continue: " Therefore, it is likely that glutamate is expelled from synaptic vesicles to provide transmission with the observed time course… " Yet, if the opening of the pore is not sufficient for fast release, and if another mechanism needs to expel the transmitter wherever it comes from, then why the opening of a vesicle would necessarily precede immediately each release? There is in fact no direct evidence either that the transmitter is released from the vesicular lumen or that release happens just after the pore opens. This …