Lecture 4: Neurotransmitters, their production, release, and localization

Introduction:

When a neuron produces an action potential, and the action potential invades the "presynaptic terminal", it causes the release of a neurotransmitter. It is this process, the production of the transmitter, the release of transmitter from the terminals, the fate of the transmitter after its release, and the localization of some specific neurotransmitters.

Post-synaptic responses in neurons are a function of the receptor to which the transmitter binds. We will address this process/ing next lecture.

The synapse and its release of transmitter

Figure 7.1A: The neurotransmitter is found in clusters of small vesicles in the terminal specializations that abut the presynaptic surface. Some vesicles even seem to fuse with the synaptic membrane.

Figure 7.1B: Indeed, the vesicles have been shown to fuse and release their contents into the space between the presynaptic and postsynaptic membranes. This has provided proof that the vesicles are indeed containers for the transmitter.

Figure 7.1C: In a "freeze-fracture" (to be explained) the vesicles are shown to be open to the space between the two membranes.

Notice that the vesicles are largely all the same size. Indeed, there is evidence that release of transmitter is "quantal". That is, transmitter is released in packets of roughly the same size. It is not put out molecule by molecule, but in these packets. Thus, since the responses are a function of the amount of transmitter released, the postsynaptic responses will be roughly quantal. That is, they will increase by integer amounts, not continuously.

Figure 7.2: The life cycle of a vesicle, and some of the events of the synapse, pre- and post-. The number events are general for all transmitters.

1) Transmitter precursors is taken up by a Na ion dependent process.

2) Synthesis of the transmitter, is either within the cytoplasm or the synaptic vesicles, depending on the particular transmitter.

3) Notice that the materials for the vesicle are transported down the axon.

5) Concentration of transmitter in vesicles.

6) Anchoring of vesicles near active zones of synapse.

7) Vesicles docked near Ca channels.

8) Depolarization of terminal membrane by action potential.

9) Voltage dependent Ca channels open and Ca ion influx near vesicle active zones.

10) Triggering of exocytosis of docked vesicles due to calcium concentration.

11) Non-quantal release of transmitter

12) Recovery of vesicle membrane from the terminal membrane

13) Fusion of vesicle membranes and

14) Recycling of vesicle membrane

Notice also the postsynaptic receptors and the degradative enzymes in the synaptic cleft.

Chapter 8: Transmitters

Figure 8.2: Modes of intercellular communication.

A. Diffuse release and non-specialized responses. The transmitter is not selectively released at a particular synapse. Rather, it is released diffusely and diffuses across distances.

B. Low resistance electrical connections which do not depend on transmitters. They depend on "tight junctions" - membranes which allow passage of charge.

C. Gap junctions - another form of tight junctions of low resistance membranes. They also will pass current.

D. Chemical synapse. These are formed by closely aligned membrane surfaces, but not tight junctions. There are specializations at the synapse as shown in Figure 7.1 which are designed to release specific transmitter(s) in response to action potentials. The postsynaptic membrane has receptors which cause responses in the postsynaptic neuron.

Criteria for a transmitter:

1. The substance must be synthesized and released from neurons.

2. The substance must be released from the terminals in an identifiable way. That is, it must be clearly identified as the substance being released.

3. The substance must reproduce the events in the postsynaptic terminal that are known to occur after nerve stimulation. And the concentrations required must be within the amounts seen at a terminal.

4. The effects in the postsynaptic terminal must be blockable by known competitive antagonists.

5. There must be appropriate active mechanisms to terminate the action of the transmitter, either by enzymes, reuptake or specific transporter mechanisms.

Figure 8.3: Life cycle of a "classical" neurotransmitter (a) acetylcholine, b) biogenic amines: serotonin, norepinepherine and dopamine, and c) amino acids, glutamate and GABA) - as opposed to gases, peptides and growth factors.

1) synthesis of transmitter

2) continued to produce mature molecule

3) transmitter is accumulated into vesicles

4) binding and recognition by postsynaptic receptors

5) OR presynaptic autoreceptors which regulate subsequent transmitter release or its production

6) transmitter reuptake or breakdown

7) OR diffusion away from cleft

8) OR reuptake into glial cells

Figure 8.6: Distribution of norepinepherine and dopamine and their projection areas. Notice that both have very large projection areas, but very different. Norephinepherine is especially wide spread.

Figure 8.7: Serotonergic neuron - same as others, but shows the steps leading to its synthesis.

Figure 8.8: Distribution and projection of serotonin - again very wide spread. Also, it is distributed by diffusion often rather than at selective synapses.

Figure 8.9: GABAergic neuron - basically the same as others, but notice that the transmitter is taken up by glial cells after release.

Figure 8.10: Glutamate neuron - similar to GABAergic neuron

Figure 8.11: Acetylcholinergic neuron - here we have enzymatic breakdown by acetylcholinesterase AChE in the cleft.

Figure 8.12: Distribution and projection areas for ACh - very large!

Functional significance is attributable to the distributions of these transmitters.

Figure 8.14: Representation of nitric oxide containing neuron. Note the differences. It freely diffuses across cell membranes and can effect other neurons or glial cells not directly apposed to the neuron. Think of it having a sphere of influence.