Influx of Ca2 Through Voltage Gated Ca2 Channels Triggers Release of Neurotransmitters

Neurotransmitters are released by exocytosis, a process in which neurotransmitter-filled synaptic vesicles fuse with the axonal membrane, releasing their contents into the synaptic cleft. The exocytosis of neurotransmitters from synaptic vesicles involves vesicle-targeting and fusion events similar to those that occur during the intracellular transport of secreted and plasma-membrane proteins (Chapter 17). Two features

M FIGURE 7-41 Structures of several small molecules that function as neurotransmitters. Except for acetylcholine, all these are amino acids (glycine and glutamate) or derived from the indicated amino acids. The three transmitters synthesized from tyrosine, which contain the catechol moiety (blue highlight), are referred to as catecholamines.

critical to synapse function differ from other secretory pathways: (a) secretion is tightly coupled to arrival of an action potential at the axon terminus, and (b) synaptic vesicles are recycled locally to the axon terminus after fusion with the plasma membrane. Figure 7-42 shows the entire cycle whereby synaptic vesicles are filled with neurotransmitter, release their contents, and are recycled.

Depolarization of the plasma membrane cannot, by itself, cause synaptic vesicles to fuse with the plasma membrane. In order to trigger vesicle fusion, an action potential must be converted into a chemical signal—namely, a localized rise in the cytosolic Ca2+ concentration. The transducers of the electric signals are voltage-gated Ca2+ channels localized to the region of the plasma membrane adjacent to the synaptic vesicles. The membrane depolarization due to arrival of an action potential opens these channels, permitting an influx

â–² FIGURE 7-42 Cycling of neurotransmitters and of synaptic vesicles in axon terminals. The entire cycle depicted here typically takes about 60 seconds. Note that several transport proteins participate in the filling of synaptic vesicles with neurotransmitter (red circles), its release by exocytosis, and subsequent reuptake from the synaptic cleft. Once synaptic-vesicle membrane proteins (e.g., pumps, antiporters, and fusion of Ca2+ ions from the extracellular medium into the axon terminal. This ion flux raises the local cytosolic Ca2 + concentration near the synaptic vesicles from <0.1 ^M, characteristic of the resting state, to 1-100 ^M. Binding of Ca2+ ions to proteins that connect the synaptic vesicle with the plasma membrane induces membrane fusion and thus ex-ocytosis of the neurotransmitter. The subsequent export of extra Ca2+ ions by ATP-powered Ca2+ pumps in the plasma membrane rapidly lowers the cytosolic Ca2+ level to that of the resting state, enabling the axon terminus to respond to the arrival of another action potential.

A simple experiment demonstrates the importance of voltage-gated Ca2+ channels in release of neurotransmitters. A preparation of neurons in a Ca2+-containing medium is treated with tetrodotoxin, a drug that blocks voltage-gated Na+ channels and thus prevents conduction of action proteins needed for exocytosis) are specifically recovered by endocytosis in clathrin-coated vesicles, the clathrin coat is depolymerized, yielding vesicles that can be filled with neurotransmitter. Unlike most neurotransmitters, acetylcholine is not recycled. See text for details. [See T Sudhof and R. Jahn, 1991, Neuron 6:665; K. Takei et al., 1996, J. Cell. Biol. 133:1237; and V. Murthy and C. Stevens, 1998, Nature 392:497.]

H+-linked antiporter

V-class H+ pump

Docking and OO Ca2+-sensing proteins

Voltage-gated Ca2+ channel

Na+-neurotransmitter symport protein

Movement to active zone

Vesicle docking at plasma membrane

Import of neurotransmitter H+

Recovery of synaptic vesicles via endocytosis 6

Cytosol of presynaptic cell

Synaptic cleft

Exocytosis of neurotransmitter triggered by influx of Ca2+

Clathrin

Reuptake of neurotransmitter

Exocytosis of neurotransmitter triggered by influx of Ca2+

Clathrin

Plasma membra

Reuptake of neurotransmitter

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