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Regulation of modes of synaptic vesicle release in control and diabetic nerve terminals

Ashton, AC; Patel, MH; Bhuva, DA; Sihra, TS; (2011) Regulation of modes of synaptic vesicle release in control and diabetic nerve terminals. In: (Proceedings) Society for Neuroscience.

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Abstract

There is much debate as to whether synaptic vesicle (SV) fusion in nerve terminals can occur via a “kiss-and-run” (KR) mode of exocytosis and this has been studied, herein, using cerebrocortical synaptosomes from adult rats. Synaptosomes were maximally loaded with FM 2-10 styryl dye under conditions that labelled all releasable SVs - this required 5 mM [Ca2+]e with the stimuli employed - and exocytosis of dye studied. Various secretagogues (high K+, 4-aminopyridine, ionomycin) were used to stimulate a single round of SV exocytosis from both the readily releasable pool (RRP) and reserve/recycling pool (RP) of SVs, looking at both FM 2-10 dye liberation and glutamate release (the major neurotransmitter present). Maximum FM 2-10 dye release requires exocytosis to occur by full fusion (FF), rather than by KR, whereas SVs can release all their glutamate even via a transiently open fusion pore. We found that the inhibition of protein phosphatase 2A caused a switch in the mode of exocytosis from KR to FF and that normally only the RRP undergoes KR whilst the RP SVs exocytose by FF. However, the use of ionomycin with 10 mM Ca2+ - a condition that produces a larger evoked increase in [Ca2+]i - could induce some of the RP to convert to a KR mode of exocytosis. Intriguingly, the protein phosphatase 2B inhibitor cyclosporine A induced the RP SVs to undergo KR rather than FF exocytosis, and such treatment also induced a larger change in evoked [Ca2+]i. Interestingly, stimulation of synaptosomes prepared from streptozotocin-treated rats - a model of type 1 diabetes - indicated that these exhibited both a larger amount of KR release and a larger change in [Ca2+]i. Clearly changes in protein phosphorylation and Ca2+ levels can play a role in the switching of the exocytotic mode. Extensive investigations have been carried out to determine the role of individual protein kinases (PKC and CAMKII) and the contribution that different voltage dependent Ca2+ channels (P, Q, N and L types) make in this switch, and enlightening comparisons have been made between terminals from control and diabetic animals. E.g. the response of these terminals to a number of inhibitors were different and this may correlate with distinct contributions that specific Ca2+ channels make in controlling the mode of exocytosis in these two terminal types. Furthermore, differences between the control and diabetic terminals are also apparent in their response to dynamin or myosin 2 inhibition. This multi-targeted approach should help elucidate the precise pathways involved in the switching between the modes of exocytosis.

Type: Proceedings paper
Title: Regulation of modes of synaptic vesicle release in control and diabetic nerve terminals
Event: Society for Neuroscience
Location: Washington, DC
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1453387
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