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Inhibitors have been key in the development of our knowledge of cellular processes.

Inhibitors have been key in the development of our knowledge of cellular processes.

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An essay for the 2011 Undergraduate Awards Competition by Fiachra Carroll. Originally submitted for Biochemistry at Trinity College, Dublin, with lecturer Derek Nolan in the category of Life Sciences
An essay for the 2011 Undergraduate Awards Competition by Fiachra Carroll. Originally submitted for Biochemistry at Trinity College, Dublin, with lecturer Derek Nolan in the category of Life Sciences

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Published by: Undergraduate Awards on Aug 29, 2012
Copyright:Attribution Non-commercial

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11/08/2013

 
Overall Introduction
Considering the fact that most if not all specific toxins producedhave co-evolved with the organism(s) that they have an effect on, it isunsurprising that the study of their specific mechanism of action can shedlight on valuable information of how cellular processes occur, and thespecific proteins or molecules involved in the physiology of the host.Nerves and neurotransmitter release are among the most popularlystudied region of physiology due to the intense effect that numerousneurotoxins have on them. Neurotoxins can have their effect either post-synaptically, affecting acetylcholine, acetyl cholinesterase, ion channels ormost frequently there effect is experienced pre-synaptically. This is doneby either binding to ion channels and altering the permeability of themembranes to certain ions, most importantly Ca2+ or by cleaving highlyconserved and very specific proteins involved in the release of neurotransmitters by exocytosis. This review is going to cover one neurotoxin
α
-latrotoxin from Black Widow Spiders
that primarily is associated with ion channels and also has aproposed part to play in second messenger signalling though that areastill remains somewhat unknown, and another set of bacterial neurotoxinswhich are purely associated with the fusion process. These are producedby Clostridial bacteria and are Botulinum neurotoxin and TetanusNeurotoxin.KEY WORDS: SNARES, BoNT/TeNT,
α
-latrotoxin, fusion
 
Fusion
ABSTRACT
Considering the fact that most if not all specific toxins producedhave co-evolved with the organism(s) that they have an effect on, it isunsurprising that the study of their specific mechanism of action can shedlight on valuable information of how cellular processes occur, and thespecific proteins or molecules involved in the physiology of the host.Fusion is the process by which two membranes come into close proximitywith one another and through still partly unknown steps combinetemporarily or permanently. This accounts for many processes like thetransport and packaging of proteins in the golgi apparatus or the insertionof transporters like aquaporins as a stimulated response to vasopressin.But this section will focus primarily on the fusion of vesicles in neuronalcells with the presynaptic membrane, and the contribution that thebacterial toxic inhibitors produced by Clostridial bacteria have given to ourunderstanding of the fusion process. These toxins have specific effects onSNAREs (Soluble N-Ethylaleimide Sensitive Factors Attachment ProteinReceptors) which are the proteins responsible for creating the interactionbetween the vesicles and the membrane with which they will fuse.
INTRODUCTION
In the 1960s and 1970s studies from several laboratories includingthe laboratory of the Nobel Prize winner, Bernard Katz, led to therealization that transmitters are packaged in vesicles and that fusion of the vesicle membrane with the synaptic plasma membrane leads totransmitter release [1]. It is now understood that several proteins areinvolved in the docking and fusion processes and that followingtransmitter release, vesicles are recycled to the endosome or refilled withneurotransmitter. It is thanks mostly to bacterial toxins that thesedevelopments in our knowledge have come about.
 
For vesicle release to occur, there needs to be a huge increase inintracellular Ca2+ (from about 100nM at resting potential compared tobetween 1.5 – 2 mM). This increase occurs when an action potentialreaches the end of a neuron, and opens the voltage sensitive calciumchannels as the membrane becomes depolarized. The following is a quote form the book written by Bernard Katz inthe mid 60s [1] “It is interesting to note certain features that the initiationof muscle contraction shares with the initiation of an action potential andwith the release of a transmitter substance at a nerve terminal. In allthree cases, the primary event is a depolarization of the cell membrane.Depolarization, however, is not a sufficient stimulus; it becomes effectivein producing its diverse results only if calcium is present, whether the finalresult be increase of sodium permeability, the facilitated release of acetylcholine quanta, or the activation of myosin molecules.”Katz saw a connection between Ca2+ and vesicle fusion but focusedmore on studying the presence of calcium rather than the flux. Hedetermined that the absence of calcium prevented release, while additionof sufficient amounts induced release.Mable Hokin and her husband Lowell were some of the firstscientists to focus on the flux of Ca2+ causing the release, and with thecombined work of Bob Michell it was determined in 1975 that the PI cyclewas essential for increasing the calcium concentration inside the cell [2].It wasn’t till 1992 that Sudhof and Jahn identified Synaptotagmin as acalcium clamp, whereby upon binding of calcium to the protein theprocess of fusion occurred to completion [3]. This was then indicated to bea preventative measure to stop spontaneous fusion rather than afacilitative protein [4].More recently, Otoferlin was proposed to be a calcium sensor similarto synaptotagmin, but specific for the cochlear hair cells, and Otoferlin hassix Ca2+ binding domains to synaptotagmins two [5]. This possibly showsa different level of control based on the amount of calcium released

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