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This Article Full Text Full Text (PDF) All Versions of this Article: 571/1/83    most recent jphysiol.2005.098319v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zamir, O. Articles by Charlton, M. P. Search for Related Content PubMed PubMed Citation Articles by Zamir, O. Articles by Charlton, M. P. Related Collections Neuroscience

¹ Physiology Department, University of Toronto, Toronto, Ontario, Canada

During exocytosis of synaptic transmitters, the fusion of highly curved synaptic vesicle membranes with the relatively planar cell membrane requires the coordinated action of several proteins. The role of membrane lipids in the regulation of transmitter release is less well understood. Since it helps to control membrane fluidity, alteration of cholesterol content may alter the fusibility of membranes as well as the function of membrane proteins. We assayed the importance of cholesterol in transmitter release at crayfish neuromuscular junctions where action potentials can be measured in the preterminal axon. Methyl-ß-cyclodextrin (MßCD) depleted axons of cholesterol, as shown by reduced filipin labelling, and cholesterol was replenished by cholesterol–MßCD complex (Ch-MßCD). MßCD blocked evoked synaptic transmission. The lack of postsynaptic effects of MßCD on the time course and amplitude of spontaneous postsynaptic potentials or on muscle resting potential allowed us to focus on presynaptic mechanisms. Intracellular presynaptic axon recordings and focal extracellular recordings at individual boutons showed that failure of transmitter release was correlated with presynaptic hyperpolarization and failure of action potential propagation. All of these effects were reversed when cholesterol was replenished with Ch-MßCD. However, focal depolarization of presynaptic boutons and administration of a Ca²⁺ ionophore both triggered transmitter release after cholesterol depletion. Therefore, both presynaptic Ca²⁺ channels and Ca²⁺-dependent exocytosis functioned after cholesterol depletion. The frequency of spontaneous quantal transmitter release was increased by MßCD but recovered when cholesterol was reintroduced. The increase in spontaneous release was not through a calcium-dependent mechanism because it persisted with intense intracellular calcium chelation. In conclusion, cholesterol levels in the presynaptic membrane modulate several key properties of synaptic transmitter release.

(Received 8 September 2005; accepted after revision 5 December 2005; first published online 8 December 2005)
Corresponding author M. P. Charlton: Physiology Department, University of Toronto, 1 King's College Circle, Room 3308, Toronto, Ontario, Canada M5S1A8. Email: milton.charlton{at}utoronto.ca

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