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How Neurons Communicate to Each Other at a Chemical Synapse?
Introduction
The discovery of how the nervous system communicates to each other at the cellular
level is one of the most astonishing works done by the neuroscientists. Based on the
process of chemical neurotransmission (communication of nervous system), drugsthat treat neurological diseases, like insomnia, depression, eating disorder, and
neurodegenerative diseases, have been developed.
The following discussion proposes the most recent theory of the process of chemical
neurotransmission between presynaptic and postsynaptic neurons. This document
will clarify the process of transmitting chemical molecules from the presynaptic to
the postsynaptic neuron for students who are currently taking college level
neurobiology or psychology classes. The first topic focuses on the presynaptic
neurons and describes the five steps of cycle of synaptic vesicles carrying the
chemical neurotransmitters for transmission. The second topic focuses on the
postsynaptic neuron and introduces two distinct receptors: Ionotropic andMetabotropic receptors.
Presynaptic Neurons: Cycle of synaptic vesicles
At chemical synapses there is a gap between presynaptic and postsynaptic neurons,
called synaptic gap (or synapse). Generally chemical synaptic transmission depends
on the diffusion of a chemical neurotransmitteracross the synapse. Thousands of
neurotransmitters are packaged inside a synaptic vesicleand released through the
process known as Exocytosis. Five steps of the cycle of synaptic vesicles before
neurotransmitters leave the presynaptic neuron will be discussed in a chronological
order.
Figure 1 The Synaptic Vesicle Cycle
http://www2.tau.ac.il/InternetFiles/Researchers/images/82_Ashery_Uri.jpg
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1) Trafficking of synaptic vesicles toward the terminal membrane
The transportation of neurotransmitters is carried out by synaptic vesicles.
Neurotransmitters reserved in the presynaptic neuron enter into the empty vesicles
through active transport, which provides energy to go against the concentration
gradient. When synaptic vesicles are filled with neurotransmitters (chemical
molecules), they cluster in the nerve terminal to dock at the active zone of thepresynaptic membrane.
2) Docking process of synaptic vesicles to the terminal membrane
Filled vesicles dock at the active zone of the presynaptic neuron, preparing to
release thousands of chemical molecules to the synaptic gap. The docking of vesicles
is done by the help of the synapsins. Synapsinsare peripheral membrane proteins
that are bound to the cytoplasmic surface of synaptic vesicles, which are utilized as a
restraint and mobilization of vesicles. After attaching to the active zone, synaptic
vesicles undergo an ATP-dependent priming reaction, which enables the vesicle to
fuse with the terminal membrane when triggered with calcium ion signal.
3) Fusion of synaptic vesicles and the terminal membrane
During a presynaptic action potential, voltage gated Ca2+channels at the active zone
opens and allows Ca2+to enter the presynaptic terminal. The gradual increase of
Ca2+concentration triggers a reaction that causes the vesicle to fuse with the
presynaptic membrane and release the neurotransmitter into the synapse, a process
known as Exocytosis. When the nerve terminal is depolarized and Ca2+ enters, the
synapsinsbecome phosphorylated (activated) by the kinase and are thus released
from the vesicles, a step that is thought to mobilize the rest of the vesicles for
another round of transmitter release. During exocytosis, additional critical protein
known as SNAREs is involved to facilitate the process.
4) Involvement of SNAREs during Exocytosis process
SNAREs are universally involved in membrane fusion, from yeast to humans. They
mediate synaptic vesicle trafficking, which is important for regulating exocytosis.
SNAREcomes in two forms: Vesicle SNAREs (v-SNARE) reside in the vesicle
membranes; Target-membrane SNAREs (t-SNARE) are present in target
membranes, such as the plasma membrane. Each synaptic vesicle contains a single
type of v-SNARE called synaptobrevin. By contrast, the presynaptic active zone
contains two types of t-SNARE proteins: Syntaxin and SNAP-25. During exocytosis
the synaptobrevin, on the synaptic vesicle, forms a tight complex with the SNAP-25,
and syntaxin, on the plasma membrane. This tight complex of synaptobrevin,
syntaxin, and SNAP-25 is known as SNARE complex.
Figure 2 SNAREs Complex during process of fusion
http://www.nature.com/nrm/journal/v3/n7/images/nrm855-f4.gif
SNARE Complex
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5) Recycling synaptic vesicle after exocytosis
After fusion, the SNAREcomplex must be disassembled for efficient vesicle recycling
to occur. A cytoplasmicATPasecalled NSFbinds to SNARE complexesvia an
adaptor protein called SNAP. NSF and SNAPuse the energy of ATP hydrolysis to
dissociate SNARE complexes, thereby regenerating free vesicles. After discharging
their contents, empty synaptic vesicles are recycled, repeating this cycle to releasemore transmitters.
Postsynaptic Receptors: Ionotropic and Metabotropic Receptors
All receptors for chemical transmitters have region exposed to the external
environment of the cell that recognizes and binds the transmitter from the
presynaptic cell. Chemical molecules produced from the presynaptic neuron diffuse
across the synapse and bind to the receptors on the postsynaptic cell membrane.
The binding of neurotransmitter activates the receptors and triggers the ion
channels of the postsynaptic neurons to open or close, thereby changing the
membrane conductance and membrane potential of the postsynaptic cell.
1) Ionotropic Receptors (Direct Receptors)
Neurotransmitters control the opening of ion channels in the postsynaptic cell
either directly or indirectly. Receptors that gate ion channels directly, referred to as
ionotropic, undergoes a conformational change that opens the channel. Due to their
relatively fast synaptic actions, ionotropic receptors are found at synapses in neural
circuits that mediate rapid behaviors, such as the stretch receptor reflex.
Figure 3 SNAP and NSF complex snipping SNARE complex after process of exocytosis
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2) Metobotropic Receptors (Indirect Receptors)
On the other hand, receptors that gate ion channels indirectly act by altering
intracellular metabolic reactions, referred to as metabotropic receptors. Activation
of these receptors often stimulates the production of second messengers, which
activate protein kinases. The protein kinases directly phosphorylate (activates) ion
channels, leading to their opening or closing. Due to its slower synaptic actions, themetabotropic receptors are known for reinforcing pathways in the process of
learning. These slower actions can modulate behavior by altering the excitability of
neurons and the strength of the synaptic connections of the neural circuitry
mediating behavior.
Summary
Chemical synaptic transmission can be divided into two steps: a transmitting step, in
which the presynaptic cell releases a chemical messenger, and a receptive step, in
which the transmitter binds to and activates the receptor molecules in the
postsynaptic cell. Synaptic vesicles go through fives steps of process before they
release a chemical messenger: Trafficking, Ducking, Fusion, Exocytosis, and Recycle.
After transmission, neurotransmitters diffuse and bind to receptors in the
postsynaptic cell. Neurotransmitters control the opening of ion channels in the
postsynaptic cell either directly or indirectly. The activation of receptors changes
the membrane conductance and membrane potential of the postsynaptic cell. Thus,
the chemical properties of the transmitter do not control the action of transmitter,
instead it heavily depends on the properties of the postsynaptic receptors that
recognize and bind the transmitter.
Figure 4 Ionotropic Receptor vs. Metabotropic Receptor
http://webvision.med.utah.edu/imageswv/GLU5.jpeg
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Glossary
ATPase:A class of enzymes that catalyze the breakdown of ATP in to ADP and a free
phosphate ion. This dephosphorylation reaction releases energy, which drives other
chemical reactions.
Chemical Neurotransmitter: Chemical substance that binds receptors in the
postsynaptic membrane of the target cell.
Exocytosis: Releasing process of neurotransmitters from the synaptic terminal.
NSF: (Also known asN-ethylmaleimide-Sensitive Factor) An ATPase involved in
dissociation SNARE complexes once membrane fusion has occurred.
Presynaptic Terminal: The distal terminations of axons, which are specialized for
the release of neurotransmitters.
SNAP: An adaptor protein that assists NSF in dissociating SNARE complexes.
SNAREs: an acronym of Soluble NSFAttachment Receptor. The role of SNARE is to
mediate vesicle fusion with the presynaptic terminal cell membrane for the
exocytosis. SNAREs can be divided into two categories: vesicle (v-SNAREs) and
target (t-SNAREs).
Synapsins: Protein that is involved in the regulation of neurotransmitter release at
synapses. Specifically involved in regulating the number of synaptic vesicles
available for exocytosis.
Synaptic Vesicle:Lipid molecules that contain molecules of neurotransmitters.
Reference
Kandel, Schwartz and Jessel,Principles of Neural Science, 5th Ed.McGraw-Hill ISBN 978-0-07-139001-8, 2013
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