In search of the fusion pore of exocytosis

Jackson, Meyer B.

doi:10.1016/j.bpc.2006.05.022

Cited by 20 publications

(16 citation statements)

References 40 publications

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“…At present, there is no indication that synaptic-vesicle fusion pores can regulate what kind of molecules can exit, but fusion pore size is widely believed to determine the rate with which neurotransmitter floods the synaptic cleft. A simple diffusion calculation shows that small fusion pores will not allow the subsynaptic neurotransmitter concentration to rise to that needed for the activation of synaptic receptors80, and this has been verified by more detailed numerical81,82 and analytical83 treatments. However, there is at present no experiment that explicitly tests the relationship between fusion pore properties (dimensions and dynamics) and a synaptic response (magnitude and time course).…”

Section: Biological Ramificationsmentioning

confidence: 91%

The fusion pores of Ca2+-triggered exocytosis

Jackson

Chapman

2008

Nat Struct Mol Biol

124

108

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The aqueous compartment inside a vesicle makes its first connection with the extracellular fluid through an intermediate structure termed the exocytotic fusion pore. Progress in exocytosis can be measured in terms of the formation and growth of the fusion pore. The fusion pore has become a major focus of research in exocytosis; sensitive biophysical measurements have provided various glimpses of what it looks like and how it behaves. Some of the principal questions about the molecular mechanism of exocytosis can be cast explicitly in terms of properties and transitions of fusion pores. This Review will present current knowledge about fusion pores in Ca 2+ -triggered exocytosis, highlight recent advances and relate questions about fusion pores to broader issues concerning how cells regulate exocytosis and how nerve terminals release neurotransmitter.During exocytosis, the merger of two biological membranes is accompanied by the mixing of the two aqueous compartments delimited by those membranes. Thus, a fluid connection forms between the two aqueous compartments at a distinct time. This connection starts out as a microscopic water-filled passage with a long narrow shape that evokes the image of a pore. The formation of the fusion pore marks a well-defined stage in the fusion process that can be studied experimentally. Likewise, the merger of the two fusing membranes marks a well-defined stage in the fusion process, which can also be studied experimentally. These two processes, aqueous content mixing and membrane merger, need not occur simultaneously, and, as will be discussed in detail below, different models of membrane fusion make different predictions about the sequence of these two events. Furthermore, since the fusion pore emerges as a structure of molecular dimensions within a specialized contact between two fusing membranes, studying the structure and dynamics of the fusion pore reveals the process of exocytosis at a fundamental level.Electron microscopy provided the first images of fusion pores with diameters of ~50 nm, but it was pointed out that these pores could have grown from something smaller1 , 2. Electrical measurements captured fusion intermediates with conductances ranging from 20 to 330 pS, and from these values one can estimate a fusion pore diameter of on the order of ~1 nm (refs. 3 -5). The structures inferred from these electrical measurements are good candidates for early-stage fusion pores. In addition to conducting ions, fusion pores also pass small neurotransmitters, and amperometric recording has revealed the flux of some of these molecules6 -8. Reports vary as to whether the initial fusion pore is well-defined and stable9 , 10, or noisy and chaotic11 -13. Thus, it is small and has protein-like dimensions, but it is not clear whether it can maintain the kind of rigid conducting state characteristic of proteinaceous ion channels. Capacitance measurements have shown that fusion pore opening is a reversible process4 , 6 , 14 -17, and amperometry has confirmed these observations6 ,...

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Section: Biological Ramificationsmentioning

confidence: 91%

The fusion pores of Ca2+-triggered exocytosis

Jackson

Chapman

2008

Nat Struct Mol Biol

124

108

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“…Bax monomers associate in the membrane to form a large pore [76], triggering downstream events in apoptosis. Like the Bcl-2 family, both Fis1 and syntaxin are also involved in processes that actively rearrange lipid bilayers: Fis1 in mitochondrial and peroxisomal fission [77], and syntaxin in formation of exocytotic fusion pores [78]. …”

Section: Membrane Insertion Of Proteins With C-terminal Transmembranementioning

confidence: 99%

Helix insertion into bilayers and the evolution of membrane proteins

Renthal

2009

Cell. Mol. Life Sci.

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Polytopic α-helical membrane proteins cannot spontaneously insert into lipid bilayers without assistance from polytopic α-helical membrane proteins that already reside in the membrane. This raises the question of how these proteins evolved. Our current knowledge of the insertion of α-helices into natural and model membranes is reviewed with the goal of gaining insight into the evolution of membrane proteins. Topics include: translocon-dependent membrane protein insertion, antibiotic peptides and proteins, in vitro insertion of membrane proteins, chaperone-mediated insertion of transmembrane helices, and C-terminal tail-anchored (TA) proteins. Analysis of the E. coli genome reveals several predicted C-terminal TA proteins that may be descendents of proteins involved in pre-cellular membrane protein insertion. Mechanisms of pre-translocon polytopic α-helical membrane protein insertion are discussed.

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“…Because the fusion pore is an important kinetic intermediate of membrane fusion, these effects of syt IV may be relevant to the mechanism of exocytosis. Furthermore, fusion pores are thought to influence the time course of synaptic transmitter release (10)(11)(12), and can selectively filter substances that are released from a vesicle (13). Thus, effects on fusion pores have implications for biological function.…”

Section: Introductionmentioning

confidence: 99%

Synaptotagmin IV Modulation of Vesicle Size and Fusion Pores in PC12 Cells

Zhang

Jackson

2010

Biophysical Journal

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Many synaptotagmins are Ca(2+)-binding membrane proteins with functions in Ca(2+)-triggered exocytosis. Synaptotagmin IV (syt IV) has no Ca(2+) binding activity, but nevertheless modulates exocytosis. Here, cell-attached capacitance recording was used to study single vesicle fusion and fission in control and syt IV overexpressing PC12 cells. Unitary capacitance steps varied widely in size, indicating that both microvesicles (MVs) and dense-core vesicles (DCVs) undergo fusion. Syt IV overexpression reduced the size of DCVs and endocytotic vesicles but not MVs. Syt IV also reduced the basal rate of Ca(2+)-induced fusion. During kiss-and-run, syt IV increased the conductance and duration of DCV fusion pores but not MV fusion pores. During full-fusion of DCVs syt IV increased the fusion pore conductance but not the duration. Syt IV overexpression increased the duration but not the conductance of fission pores during endocytosis. The effects of syt IV on fusion pores in PC12 cells resembled the effects on fusion pores in peptidergic nerve terminals. However, differences between these and results obtained with amperometry may indicate that amperometry and capacitance detect the fusion of different populations of vesicles. The effects of syt IV on fusion pores are discussed in terms of structural models and kinetic mechanisms.

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In search of the fusion pore of exocytosis

Cited by 20 publications

References 40 publications

The fusion pores of Ca2+-triggered exocytosis

The fusion pores of Ca2+-triggered exocytosis

Helix insertion into bilayers and the evolution of membrane proteins

Synaptotagmin IV Modulation of Vesicle Size and Fusion Pores in PC12 Cells

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