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Regulation of synaptic vesicle docking by different classes of macromolecules in active zone material.

Szule JA, Harlow ML, Jung JH, De-Miguel FF, Marshall RM, McMahan UJ - PLoS ONE (2012)

Bottom Line: The docking of synaptic vesicles at active zones on the presynaptic plasma membrane of axon terminals is essential for their fusion with the membrane and exocytosis of their neurotransmitter to mediate synaptic impulse transmission.We conclude that vesicle movement toward and maintenance at docking sites on the presynaptic membrane are directed by an orderly succession of stable interactions between the vesicles and distinct classes of AZM macromolecules positioned at different distances from the membrane.Establishing the number, arrangement and sequence of association of AZM macromolecules involved in vesicle docking provides an anatomical basis for testing and extending concepts of docking mechanisms provided by biochemistry.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT
The docking of synaptic vesicles at active zones on the presynaptic plasma membrane of axon terminals is essential for their fusion with the membrane and exocytosis of their neurotransmitter to mediate synaptic impulse transmission. Dense networks of macromolecules, called active zone material, (AZM) are attached to the presynaptic membrane next to docked vesicles. Electron tomography has shown that some AZM macromolecules are connected to docked vesicles, leading to the suggestion that AZM is somehow involved in the docking process. We used electron tomography on the simply arranged active zones at frog neuromuscular junctions to characterize the connections of AZM to docked synaptic vesicles and to search for the establishment of such connections during vesicle docking. We show that each docked vesicle is connected to 10-15 AZM macromolecules, which fall into four classes based on several criteria including their position relative to the presynaptic membrane. In activated axon terminals fixed during replacement of docked vesicles by previously undocked vesicles, undocked vesicles near vacated docking sites on the presynaptic membrane have connections to the same classes of AZM macromolecules that are connected to docked vesicles in resting terminals. The number of classes and the total number of macromolecules to which the undocked vesicles are connected are inversely proportional to the vesicles' distance from the presynaptic membrane. We conclude that vesicle movement toward and maintenance at docking sites on the presynaptic membrane are directed by an orderly succession of stable interactions between the vesicles and distinct classes of AZM macromolecules positioned at different distances from the membrane. Establishing the number, arrangement and sequence of association of AZM macromolecules involved in vesicle docking provides an anatomical basis for testing and extending concepts of docking mechanisms provided by biochemistry.

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Schematized 3-D arrangement of classes of AZM macromolecules throughout the depth of the resting active zone.A) View includes the transverse, horizontal and median planes of the active zone (see Figure 1C). Core macromolecules include beams (brown gold), steps (grey) and masts (dark green). Macromolecules connecting core macromolecules to synaptic vesicles (dark blue) and the presynaptic membrane (pale blue) along with channels (frosted green) in the membrane, include ribs (yellow gold), pegs (orange gold), pins (copper), spars (red), booms (purple), and topmasts (light green).The presynaptic membrane and the docked vesicles in the row on the right are transparent to expose the extent of the AZM connections. B) View from the median plane of the active zone toward the left row of docked vesicles in A. C) View from beyond the active zone toward the left row of docked vesicles in A.
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pone-0033333-g011: Schematized 3-D arrangement of classes of AZM macromolecules throughout the depth of the resting active zone.A) View includes the transverse, horizontal and median planes of the active zone (see Figure 1C). Core macromolecules include beams (brown gold), steps (grey) and masts (dark green). Macromolecules connecting core macromolecules to synaptic vesicles (dark blue) and the presynaptic membrane (pale blue) along with channels (frosted green) in the membrane, include ribs (yellow gold), pegs (orange gold), pins (copper), spars (red), booms (purple), and topmasts (light green).The presynaptic membrane and the docked vesicles in the row on the right are transparent to expose the extent of the AZM connections. B) View from the median plane of the active zone toward the left row of docked vesicles in A. C) View from beyond the active zone toward the left row of docked vesicles in A.

Mentions: We show that each docked vesicle at active zones in resting axon terminals of the frog’s NMJ is connected to multiple members of four classes of filamentous AZM macromolecules (Figure 11). The connections formed by two classes, ribs and pins, are adjacent to the presynaptic membrane and surround the domain of the vesicle that will fuse with the presynaptic membrane during synaptic transmission. The connections formed by the third class, spars, are further from the presynaptic membrane, and the connections formed by the fourth class, booms, are furthest from the membrane. At active zones in axon terminals fixed during synaptic activity, undocked vesicles within ∼50 nm vertical to sites on the presynaptic membrane formerly occupied by docked vesicles are connected to the same classes of AZM macromolecules as docked vesicles. The number of classes to which the undocked vesicles are attached is inversely related to the vesicles’ distance from the membrane. The furthest vesicles are connected primarily to the booms, nearer vesicles are connected primarily to both booms and spars, while the nearest vesicles are connected to the same assortment of classes as docked vesicles; booms, spars, ribs and pins (Figure 12). The number of connections formed by each class on undocked vesicles and the mean distance of their connection sites from each other is the same as for docked vesicles in resting axon terminals. We conclude that AZM directs undocked vesicles toward docking sites on the presynaptic membrane through a succession of specific macromolecular interactions with the vesicles, and that these same interactions persist to help hold docked vesicles in position.


Regulation of synaptic vesicle docking by different classes of macromolecules in active zone material.

Szule JA, Harlow ML, Jung JH, De-Miguel FF, Marshall RM, McMahan UJ - PLoS ONE (2012)

Schematized 3-D arrangement of classes of AZM macromolecules throughout the depth of the resting active zone.A) View includes the transverse, horizontal and median planes of the active zone (see Figure 1C). Core macromolecules include beams (brown gold), steps (grey) and masts (dark green). Macromolecules connecting core macromolecules to synaptic vesicles (dark blue) and the presynaptic membrane (pale blue) along with channels (frosted green) in the membrane, include ribs (yellow gold), pegs (orange gold), pins (copper), spars (red), booms (purple), and topmasts (light green).The presynaptic membrane and the docked vesicles in the row on the right are transparent to expose the extent of the AZM connections. B) View from the median plane of the active zone toward the left row of docked vesicles in A. C) View from beyond the active zone toward the left row of docked vesicles in A.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3306385&req=5

pone-0033333-g011: Schematized 3-D arrangement of classes of AZM macromolecules throughout the depth of the resting active zone.A) View includes the transverse, horizontal and median planes of the active zone (see Figure 1C). Core macromolecules include beams (brown gold), steps (grey) and masts (dark green). Macromolecules connecting core macromolecules to synaptic vesicles (dark blue) and the presynaptic membrane (pale blue) along with channels (frosted green) in the membrane, include ribs (yellow gold), pegs (orange gold), pins (copper), spars (red), booms (purple), and topmasts (light green).The presynaptic membrane and the docked vesicles in the row on the right are transparent to expose the extent of the AZM connections. B) View from the median plane of the active zone toward the left row of docked vesicles in A. C) View from beyond the active zone toward the left row of docked vesicles in A.
Mentions: We show that each docked vesicle at active zones in resting axon terminals of the frog’s NMJ is connected to multiple members of four classes of filamentous AZM macromolecules (Figure 11). The connections formed by two classes, ribs and pins, are adjacent to the presynaptic membrane and surround the domain of the vesicle that will fuse with the presynaptic membrane during synaptic transmission. The connections formed by the third class, spars, are further from the presynaptic membrane, and the connections formed by the fourth class, booms, are furthest from the membrane. At active zones in axon terminals fixed during synaptic activity, undocked vesicles within ∼50 nm vertical to sites on the presynaptic membrane formerly occupied by docked vesicles are connected to the same classes of AZM macromolecules as docked vesicles. The number of classes to which the undocked vesicles are attached is inversely related to the vesicles’ distance from the membrane. The furthest vesicles are connected primarily to the booms, nearer vesicles are connected primarily to both booms and spars, while the nearest vesicles are connected to the same assortment of classes as docked vesicles; booms, spars, ribs and pins (Figure 12). The number of connections formed by each class on undocked vesicles and the mean distance of their connection sites from each other is the same as for docked vesicles in resting axon terminals. We conclude that AZM directs undocked vesicles toward docking sites on the presynaptic membrane through a succession of specific macromolecular interactions with the vesicles, and that these same interactions persist to help hold docked vesicles in position.

Bottom Line: The docking of synaptic vesicles at active zones on the presynaptic plasma membrane of axon terminals is essential for their fusion with the membrane and exocytosis of their neurotransmitter to mediate synaptic impulse transmission.We conclude that vesicle movement toward and maintenance at docking sites on the presynaptic membrane are directed by an orderly succession of stable interactions between the vesicles and distinct classes of AZM macromolecules positioned at different distances from the membrane.Establishing the number, arrangement and sequence of association of AZM macromolecules involved in vesicle docking provides an anatomical basis for testing and extending concepts of docking mechanisms provided by biochemistry.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, California, United States of America.

ABSTRACT
The docking of synaptic vesicles at active zones on the presynaptic plasma membrane of axon terminals is essential for their fusion with the membrane and exocytosis of their neurotransmitter to mediate synaptic impulse transmission. Dense networks of macromolecules, called active zone material, (AZM) are attached to the presynaptic membrane next to docked vesicles. Electron tomography has shown that some AZM macromolecules are connected to docked vesicles, leading to the suggestion that AZM is somehow involved in the docking process. We used electron tomography on the simply arranged active zones at frog neuromuscular junctions to characterize the connections of AZM to docked synaptic vesicles and to search for the establishment of such connections during vesicle docking. We show that each docked vesicle is connected to 10-15 AZM macromolecules, which fall into four classes based on several criteria including their position relative to the presynaptic membrane. In activated axon terminals fixed during replacement of docked vesicles by previously undocked vesicles, undocked vesicles near vacated docking sites on the presynaptic membrane have connections to the same classes of AZM macromolecules that are connected to docked vesicles in resting terminals. The number of classes and the total number of macromolecules to which the undocked vesicles are connected are inversely proportional to the vesicles' distance from the presynaptic membrane. We conclude that vesicle movement toward and maintenance at docking sites on the presynaptic membrane are directed by an orderly succession of stable interactions between the vesicles and distinct classes of AZM macromolecules positioned at different distances from the membrane. Establishing the number, arrangement and sequence of association of AZM macromolecules involved in vesicle docking provides an anatomical basis for testing and extending concepts of docking mechanisms provided by biochemistry.

Show MeSH
Related in: MedlinePlus