- Title
- Small molecules demonstrate the role of dynamin as a bi-directional regulator of the exocytosis fusion pore and vesicle release
- Creator
- Jackson, J.; Papadopulos, A.; Meunier, F. A.; McCluskey, A.; Robinson, P. J.; Keating, D. J.
- Relation
- NHMRC .569596 & ARC.LE0882864 http://purl.org/au-research/grants/nhmrc/569596
- Relation
- Molecular Psychiatry Vol. 20, Issue 7, p. 810-819
- Publisher Link
- http://dx.doi.org/10.1038/mp.2015.56
- Publisher
- Nature Publishing Group
- Resource Type
- journal article
- Date
- 2015
- Description
- Hormones and neurotransmitters are stored in specialised vesicles and released from excitable cells through exocytosis. During vesicle fusion with the plasma membrane, a transient fusion pore is created that enables transmitter release. The protein dynamin is known to regulate fusion pore expansion (FPE). The mechanism is unknown, but requires its oligomerisation-stimulated GTPase activity. We used a palette of small molecule dynamin modulators to reveal bi-directional regulation of FPE by dynamin and vesicle release in chromaffin cells. The dynamin inhibitors Dynole 34-2 and Dyngo 4a and the dynamin activator Ryngo 1-23 reduced or increased catecholamine released from single vesicles, respectively. Total internal reflection fluorescence (TIRF) microscopy demonstrated that dynamin stimulation with Ryngo 1-23 reduced the number of neuropeptide Y (NPY) kiss-and-run events, but not full fusion events, and slowed full fusion release kinetics. Amperometric stand-alone foot signals, representing transient kiss-and-run events, were less frequent but were of longer duration, similarly to full amperometric spikes and pre-spike foot signals. These effects are not due to alterations in vesicle size. Ryngo 1-23 action was blocked by inhibitors of actin polymerisation or myosin II. Therefore, we demonstrate using a novel pharmacological approach that dynamin not only controls FPE during exocytosis, but is a bi-directional modulator of the fusion pore that increases or decreases the amount released from a vesicle during exocytosis if it is activated or inhibited, respectively. As such, dynamin has the ability to exquisitely fine-tune transmitter release.
- Subject
- molecules; dynamin; skin; exocytosis
- Identifier
- http://hdl.handle.net/1959.13/1339614
- Identifier
- uon:28297
- Identifier
- ISSN:1476-5578
- Language
- eng
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