Vesicle fusion
Encyclopedia
Vesicle fusion is the merging of a vesicle with other vesicles
or a part of a cell membrane
. In the latter case, it is the end stage of secretion
from secretory vesicles, where their contents are expelled from the cell through exocytosis
at the porosome
. Vesicles can also fuse with other target cell compartments, such as a lysosome
.
Vesicle fusion may depend on SNARE proteins
in the presence of increased intracellular calcium
(Ca2+) concentration.
or a mixture have been studied by physical chemists. Cardiolipin is found mainly in mitochondrial membranes, and calcium ions play an important role in the respiratory processes mediated by the mitochondrion
. The forces involved have been postulated to explain this process in terms of nucleation for agglomeration of smaller supramolecular entities or phase changes in the structure of the biomembranes.
fusion, the vesicle must be within a few nanometers of the target membrane for the fusion process to begin. This closeness allows the cell wall and the vesicle to exchange lipids which is mediated by certain proteins which remove water that comes between the forming junction. Once the vesicle is in position it must wait until Ca2+ enters the cell by the propagation of an action potential
to the presynaptic membrane. Ca2+ binds to specific proteins, one of which is synaptotagmin
, in neurons which triggers the complete fusion of the vesicle with the target membrane.
SNARE proteins are also thought to help mediate which membrane is the target of which vesicle.
Assembly of the SNAREs into the "trans" complexes likely bridges the opposing lipid bilayers of membranes belonging to cell and secretory granule, bringing them in proximity and inducing their fusion. The influx of calcium into the cell triggers the completion of the assembly reaction, which is mediated by an interaction between the putative calcium sensor, synaptotagmin
, with membrane lipids and/or the partially assembled
SNARE complex.
According to the "zipper" hypothesis, the complex assembly starts at the N-terminal parts of SNARE motifs and proceeds towards the C-termini that anchor interacting proteins in membranes. Formation of the "trans"-SNARE complex proceeds through an intermediate complex composed of SNAP-25 and syntaxin-1, which later accommodates synaptobrevin-2 (the quoted syntaxin and synaptobrevin isotypes participate in neuronal neuromediator release).
Based on the stability of the resultant cis-SNARE complex, it has been postulated that energy released during the assembly process serves as a means for overcoming the repulsive forces between the membranes. There are several models that propose explanation of a subsequent step – the formation of stalk and fusion pore
, but the exact nature of these processes remains debated. It has, however, been proven that in vitro syntaxin
per se is sufficient to drive spontaneous calcium independent fusion of synaptic vesicles containing v-SNAREs. This suggests that in Ca2+-dependent neuronal exocytosis synaptotagmin
is a dual regulator, in absence of Ca2+ ions to inhibit SNARE dynamics, while in presence of Ca2+ ions to act as agonist in the membrane fusion process.
s, some neurochemists have suggested that vesicles occasionally may not completely fuse with presynaptic membranes in neurotransmitter release into the synaptic cleft. The controversy lies in whether or not endocytosis
always occurs in vesicle reforming after release of the neurotransmitter. Another proposed mechanism for release of vesicle contents into extracellular fluid is called the "kiss and go" mechanism.
There is some indication that vesicles may only form a small pore in the presynaptic membrane allowing contents to be released by standard diffusion for a short while before retreating back into the presynaptic cell. This mechanism may be a way around clathrin-mediated endocytosis. It is also proposed that the vesicle does not need to return to an endosome
to refill, though it is not thoroughly understood the mechanism by which is would refill. It should also be noted that this does not exclude full vesicle fusion, but only states that both mechanisms may operate in synaptic clefts.
"Kiss and Go" has been shown to occur in endocrine cells, though it has not been directly witnessed in synaptic gaps.
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
or a part of a cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
. In the latter case, it is the end stage of secretion
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
from secretory vesicles, where their contents are expelled from the cell through exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
at the porosome
Porosome
Porosomes or fusion pores are cup-shaped structures in the cell membranes of eukaryotic cells where vesicles dock in the process of vesicle fusion and secretion. These structures are about 150 nanometers in diameter and contain many different types of protein, especially SNARE proteins that mediate...
. Vesicles can also fuse with other target cell compartments, such as a lysosome
Lysosome
thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
.
Vesicle fusion may depend on SNARE proteins
SNARE (protein)
SNARE proteins are a large protein superfamily consisting of more than 60 members in yeast and mammalian cells....
in the presence of increased intracellular calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
(Ca2+) concentration.
Triggers
Stimuli that trigger vesicle fusion act by increasing intracellular Ca2+.- Synaptic vesicleSynaptic vesicleIn a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
s commit vesicle fusion by a nerve impulse reaching the synapse, activating voltage-dependent calcium channelVoltage-dependent calcium channelVoltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+...
s that cause influx of Ca2+ into the cell. - In the endocrine systemEndocrine systemIn physiology, the endocrine system is a system of glands, each of which secretes a type of hormone directly into the bloodstream to regulate the body. The endocrine system is in contrast to the exocrine system, which secretes its chemicals using ducts. It derives from the Greek words "endo"...
, many hormones are released by their releasing hormoneReleasing hormoneA releasing hormone or releasing factor is a hormone whose main purpose is to control the release of another hormone. The main releasing hormones secreted by the hypothalamus are:*Thyrotropin-releasing hormone ,...
s binding to G protein coupled receptors coupled to the Gq alpha subunitGq alpha subunitGq protein or Gq/11 is a heterotrimeric G protein subunit that activates phospholipase C . PLC in turn hydrolyzes Phosphatidylinositol 4,5-bisphosphate to diacyl glycerol and inositol triphosphate signal transduction pathway...
, activating the IP3/DAG pathway to increase Ca2+. Examples of this mechanism include:- Gonadotropin releasing hormone
- Thyrotropin releasing hormone
- Growth hormone releasing hormoneGrowth hormone releasing hormoneGrowth-hormone-releasing hormone , also known as growth-hormone-releasing factor , somatoliberin or somatocrinin, is a releasing hormone for growth hormone...
(minor pathway - main one is cAMP dependent pathwayCAMP dependent pathwayIn the field of molecular biology, the cAMP-dependent pathway, also known as the adenylyl cyclase pathway, is a G protein-coupled receptor-triggered signaling cascade used in cell communication.-Mechanism:...
)
Model systems
Model systems consisting of a single phospholipidPhospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
or a mixture have been studied by physical chemists. Cardiolipin is found mainly in mitochondrial membranes, and calcium ions play an important role in the respiratory processes mediated by the mitochondrion
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
. The forces involved have been postulated to explain this process in terms of nucleation for agglomeration of smaller supramolecular entities or phase changes in the structure of the biomembranes.
Synaptic Cleft Fusion
In synaptic vesicleSynaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
fusion, the vesicle must be within a few nanometers of the target membrane for the fusion process to begin. This closeness allows the cell wall and the vesicle to exchange lipids which is mediated by certain proteins which remove water that comes between the forming junction. Once the vesicle is in position it must wait until Ca2+ enters the cell by the propagation of an action potential
Action potential
In physiology, an action potential is a short-lasting event in which the electrical membrane potential of a cell rapidly rises and falls, following a consistent trajectory. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, and...
to the presynaptic membrane. Ca2+ binds to specific proteins, one of which is synaptotagmin
Synaptotagmin
Synaptotagmins constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region , a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 15 members in the mammalian synaptotagmin family...
, in neurons which triggers the complete fusion of the vesicle with the target membrane.
SNARE proteins are also thought to help mediate which membrane is the target of which vesicle.
SNARE Protein and Membrane Specificity
Synaptotagmin
Synaptotagmins constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region , a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 15 members in the mammalian synaptotagmin family...
, with membrane lipids and/or the partially assembled
SNARE complex.
According to the "zipper" hypothesis, the complex assembly starts at the N-terminal parts of SNARE motifs and proceeds towards the C-termini that anchor interacting proteins in membranes. Formation of the "trans"-SNARE complex proceeds through an intermediate complex composed of SNAP-25 and syntaxin-1, which later accommodates synaptobrevin-2 (the quoted syntaxin and synaptobrevin isotypes participate in neuronal neuromediator release).
Based on the stability of the resultant cis-SNARE complex, it has been postulated that energy released during the assembly process serves as a means for overcoming the repulsive forces between the membranes. There are several models that propose explanation of a subsequent step – the formation of stalk and fusion pore
Porosome
Porosomes or fusion pores are cup-shaped structures in the cell membranes of eukaryotic cells where vesicles dock in the process of vesicle fusion and secretion. These structures are about 150 nanometers in diameter and contain many different types of protein, especially SNARE proteins that mediate...
, but the exact nature of these processes remains debated. It has, however, been proven that in vitro syntaxin
Syntaxin
Syntaxins are a family of membrane integrated Q-SNARE proteins participating in exocytosis.- Domains :Syntaxins possess a single C-terminal transmembrane domain, a SNARE domain , and an N-terminal regulatory domain ....
per se is sufficient to drive spontaneous calcium independent fusion of synaptic vesicles containing v-SNAREs. This suggests that in Ca2+-dependent neuronal exocytosis synaptotagmin
Synaptotagmin
Synaptotagmins constitute a family of membrane-trafficking proteins that are characterized by an N-terminal transmembrane region , a variable linker, and two C-terminal C2 domains - C2A and C2B. There are 15 members in the mammalian synaptotagmin family...
is a dual regulator, in absence of Ca2+ ions to inhibit SNARE dynamics, while in presence of Ca2+ ions to act as agonist in the membrane fusion process.
Kiss and Go Hypothesis
In synaptic vesicleSynaptic vesicle
In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
s, some neurochemists have suggested that vesicles occasionally may not completely fuse with presynaptic membranes in neurotransmitter release into the synaptic cleft. The controversy lies in whether or not endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
always occurs in vesicle reforming after release of the neurotransmitter. Another proposed mechanism for release of vesicle contents into extracellular fluid is called the "kiss and go" mechanism.
There is some indication that vesicles may only form a small pore in the presynaptic membrane allowing contents to be released by standard diffusion for a short while before retreating back into the presynaptic cell. This mechanism may be a way around clathrin-mediated endocytosis. It is also proposed that the vesicle does not need to return to an endosome
Endosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...
to refill, though it is not thoroughly understood the mechanism by which is would refill. It should also be noted that this does not exclude full vesicle fusion, but only states that both mechanisms may operate in synaptic clefts.
"Kiss and Go" has been shown to occur in endocrine cells, though it has not been directly witnessed in synaptic gaps.
See also
- SNARESNARE (protein)SNARE proteins are a large protein superfamily consisting of more than 60 members in yeast and mammalian cells....
- Presynaptic active zoneActive zoneThe active zone is a term first used by Couteaux and Pecot-Dechavassinein in 1970 and is defined in the neuron as the site of neurotransmitter release. Neurons contain structures called synapses that allow for the communication from one neuron to another...
- Liposomes used as models for artificial cells in membrane fusion studies.