Eng Project _4 Final

5/26/2018 Eng Project _4 Final

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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

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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

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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

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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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Eng Project _4 Final