Katz’s brilliant work built on George Palade’s (1912–2008) studie

Katz’s brilliant work built on George Palade’s (1912–2008) studies on vesicular trafficking (Palay and Palade, 1955) and initiated a series of elegant electrophysiological experiments that characterized the process of synaptic transmission in exquisite detail. Among others, these studies revealed that Ca2+ triggers release in a highly cooperative manner (Dodge and Rahamimoff, 1967) within a few hundred microseconds (Sabatini and Regehr, 1996), which is not much slower than the opening of a voltage-gated ion channel. C59 wnt datasheet What molecular mechanisms enable fast vesicle fusion at a synapse, however, remained a mystery until molecular

biology allowed mechanistic dissection of vesicle fusion and its control by Ca2+ (reviewed in Südhof and Rothman, 2009). Katz’s work posed three basic questions: • How do vesicles fuse? This general question transcends neurobiology and is important for all areas of vesicle traffic selleck inhibitor and cell biology since membrane fusion is a universal process in eukaryotic cells. These three questions lie at the heart of a

molecular understanding of synaptic transmission. As described below, we now have a plausible framework of answers to these three questions, although much remains to be done. In the following, I will first provide a brief broad outline of the general release machinery (Figure 1) and then discuss in greater detail selected questions that in my personal view are particularly interesting. Due to space constraints, I do not aim to provide a comprehensive discussion of the field, and I apologize for the many omissions I am bound to commit. Moreover, owing to the same space constraints, I will focus on physiological studies. In particular, I am unable to give appropriate consideration to PD184352 (CI-1040) the many elegant liposome fusion studies that have recently been performed; for a more complete treatment of this subject, please see Brunger et al. (2009) and Marsden et al. (2011). Work over the lifetime of Neuron—two

and a half decades!—has produced a general framework for understanding neurotransmitter release that will be briefly summarized below ( Figure 1; see also reviews by Rizo and Rosenmund, 2008, Kochubey et al., 2011 and Mohrmann and Sørensen, 2012). Intracellular membrane fusion is generally mediated by SNARE proteins (for “soluble NSF attachment receptor proteins”) and SM proteins (for “Sec1/Munc18-like proteins”) that undergo a cycle of association and dissociation during the fusion reaction ( Figure 2). At the synapse, the vesicular SNARE protein synaptobrevin (aka VAMP) forms a complex with the plasma membrane SNARE proteins syntaxin-1 and SNAP-25 ( Söllner et al., 1993a). Prior to SNARE complex formation, syntaxin-1 is present in a closed conformation that cannot engage in SNARE complex formation; syntaxin-1 has to open for SNARE complex assembly to proceed ( Dulubova et al., 1999 and Misura et al., 2000).

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