Study guidelines
- 1.
Contrast electrical and chemical synapses and describe the differences between inotropic receptors and metabotropic receptors.
- 2.
List the three second messenger systems and the functions of a second messenger.
- 3.
List the criteria that must be fulfilled before a substance can be considered a neurotransmitter.
- 4.
List the major types of neurotransmitters, and provide an example of each.
- 5.
Describe the steps that occur when a transmitter binds to an ionotropic receptor.
- 6.
Give examples of the various mechanisms used to terminate the action of a neurotransmitter or to recycle them.
Electrical synapses
Electrical synapses are scarce in the mammalian nervous system. As seen in Figure 8.1 , they consist of gap junctions (nexuses) between dendrites or somas of contiguous neurons, where there is cytoplasmic continuity through 1.5-nm channels. No transmitter is involved, and there is no synaptic delay.
The gap junctions are bridged by tightly packed ion channels, each comprising mirror image pairs of connexons, which are transmembrane protein groups (connexins) arranged hexagonally around an ion pore. Wedge-shaped connexin subunits bordering each ion pore are closely apposed when the neurons are inactive. Action potentials passing along the cell membrane cause the subunits to rotate individually, creating a pore large enough to permit free diffusion of ions and small molecules down their concentration gradients.
The overall function of these gap junctions is to ensure synchronous activity of neurons with a common action. An example is the inspiratory centre in the medulla oblongata, where all the cells exhibit synchronous discharge during inspiration. A second example is among neuronal circuits controlling saccades, where the gaze darts from one object of interest to another.
Chemical synapses
Transmitter release ( Table 8.1 and Figure 8.2 )
In resting nerve terminals, synaptic vesicles accumulate in the active zones, where they are tethered to the presynaptic densities by strands of docking proteins, including actin. With the arrival of action potentials, voltage-gated calcium (Ca 2 + ) channels located immediately adjacent to the active zone in the presynaptic membrane are opened, leading to instant flooding of the active zone with Ca 2 + ions. These ions interact with several proteins in both the vesicle and the active zone, leading to vesicle fusion and neurotransmitter release.
| Named Protein | Function |
|---|---|
| Actin | Brings vesicle into contact with presynaptic membrane |
| Calmodulin | Expels vesicle content into synaptic cleft |
| Clathrin | Withdraws vesicle membrane from synaptic cleft |
| Dynamin | Pinches the neck of the developing vesicle to complete its separation |
| Ligand | Receptor protein that binds with the transmitter molecule |
| Synaptophysin | Creates the membrane fusion pore |
Vesicle fusion begins with the interaction of vesicle SNARE proteins (v-SNARE) and a pair of presynaptic membrane proteins (t-SNARES) to form a tight complex. The necessary metabolic components that trigger vesicle fusion are embedded in the active zone. A critical protein for these components is a large, multidomain protein called RIM that binds to Rab3, a GTP-binding protein on synaptic vesicles. Other proteins are required for vesicle fusion and the release of neurotransmitters. These synaptic components include synaptic vesicle proteins (e.g. synaptotagmin, synaptobrevin, synaptophysin, and synapsins), proteins associated with synaptic vesicles (e.g. amphiphysin, dynamin, and CaM kinases), synaptic plasma membrane proteins (e.g. syntaxins, neurexins, and SNAP-25), and associated cytosolic proteins (e.g. complexins, SNAPs, and NSF).
Many of the identified synaptic proteins have distinctive roles in the excitation–secretion coupling and synaptic vesicle recovery mechanisms underlying synaptic transmission. Intricate models of the molecular machinery responsible for excitation–secretion coupling and neurotransmission at the synapse have been developed through various techniques. These and other local protein responses to Ca 2 + entry are extremely rapid, and the time between Ca 2 + entry and transmitter expulsion is less than 1 ms. In the case of small synaptic vesicles such as those containing glutamate or γ-aminobutyric acid (GABA), single spikes are sufficient to yield some transmitter release. In the case of peptidergic neurons, impulse frequencies of 10 Hz or more are required to induce typically slow (delay of 50 ms or more) transmitter release from the large, dense-cored vesicles. Therefore the amount of transmitter released from a neuron is not fixed but can be modified by both intrinsic and extrinsic modulatory processes.
Target cell receptor binding
Transmitter molecules bind with receptor protein molecules in the postsynaptic membrane. The two main categories of receptors are ionotropic and metabotropic . Each category contains some receptors whose activation leads to the opening of ion pores and others whose activation leads to their closure.
Ionotropic receptors
Ionotropic receptors are characterised by the presence of an ion channel within each receptor macromolecule ( Figure 8.3 ). The transmitter binds with its specific receptor facing the synaptic cleft, causing it to change its conformational state, normally opening a closed channel. Ionotropic receptor channels are said to be transmitter-gated , or ligand – gated , signifying their capacity to bind a transmitter molecule or a drug substitute. As soon as the transmitter dissociates from the receptor or is broken down, the channel reverts to its original state (closes).
In Figure 8.3A , the excitatory channel has been opened by the transmitter, causing a major influx of sodium ions (Na + ) and a minor efflux of potassium ions (K + ); the net result is an excitatory postsynaptic potential (EPSP) that depolarises the membrane. A larger depolarisation can be achieved by opening multiple transmitter-gated channels, resulting in summation and possibly reaching the threshold value to trigger an action potential. In Figure 8.3B , the EPSP is followed immediately by an inhibitory postsynaptic potential (IPSP) that hyperpolarises the membrane to − 70 mV, the chloride (Cl − ) equilibrium potential. A larger hyperpolarisation can be achieved by opening a K + channel, which has an equilibrium potential of − 80 mV.
Ionotropic receptors are called fast receptors because of their immediate but brief effects on ion channels.
Metabotropic receptors
Metabotropic receptors are so called because many are capable of generating multiple metabolic effects within the cytoplasm of the neuron. The receptor macromolecule is a transmembrane protein devoid of an ion channel. Its function is initiated by the binding of a transmitter to its extracellular receptor site. This causes a change in the conformational state of the protein, activating one of the attached subunits (α or β subunit) that detaches and moves along the inner surface of the membrane. The subunits are called G proteins , because most bind with guanine nucleotides such as guanine triphosphate (GTP) or guanine diphosphate (GDP) . Their action on ion channels is usually indirect, via a second messenger system . However, some G proteins activate ion channels directly (see later).
A G protein with a stimulatory effect is known as G s protein , and that with an inhibitory effect is known as G i protein . Because of the numerous steps involved, metabotropic receptors are in general slow receptors. Membrane channel effects may continue for hundreds of milliseconds after a single stimulus. Additionally, the creation of intracellular second messengers can alter the excitability properties of neurons.
Three second messenger systems are well recognised.
- 1.
The cyclic adenosine monophosphate (cAMP) system , responsible for phosphorylation of proteins.
- 2.
The phosphoinositol system , responsible for liberating Ca 2 + from cytoplasmic stores.
- 3.
The arachidonic acid system , responsible for production of arachidonic acid metabolites.
cAMP system
In the examples shown in Figure 8.4 , transmitter–receptor binding releases the α subunit of a G s protein, leaving it free to link with GTP, which in turn facilitates adenylate cyclase to convert adenosine triphosphate (ATP) to cAMP. The newly formed cAMP can now dissociate within the cell as the second messenger. Protein kinase A in the membrane is stimulated by cAMP to transfer phosphate ions from ATP to an ion channel, causing its pore to open and to allow Na + ions to enter, thus initiating depolarisation of the target neuron. When the G s protein is switched off, the membrane-attached enzyme protein phosphatase catalyses the extraction of phosphate ions, resulting in pore closure.
Phosphoinositol system
In the example shown in Figure 8.5 , activation of another kind of G s protein α subunit causes the effector enzyme phospholipase C to split a membrane phospholipid (PIP 2 ) into a pair of second messengers: diacylglycerol (DAG) and inositol triphosphate (IP 3 ). DAG activates protein kinase C, which initiates protein phosphorylation. IP 3 diffuses into the cytosol, where it opens Ca 2 + -gated channels, mainly in nearby membranes of smooth endoplasmic reticulum. The Ca 2 + ions activate certain Ca 2 + -dependent enzymes downstream, resulting in opening and/or closing of ion channels and possibly crossing the nuclear envelope to alter gene expression and protein production (see ‘ gene transcription effects ’ below).
Arachidonic acid system
This is described later, in connection with histamine.
Gene transcription effects
It is also well established that the reflex responses to repetitive stimuli may be either progressively increased (a state of sensitisation , usually induced by noxious stimuli) or diminished (a state of habituation, induced by harmless stimuli). Animal experiments investigating reflex arcs involving sets of sensory neurons, motor neurons, and interneurons have shown that a characteristic of sensitisation is the development of additional synaptic contacts between the interneurons and the motor neurons, together with additional transmitter synthesis and release. Characteristic of habituation is a reduction of transmitter synthesis and release. All these changes result from alterations of gene transcription. Repetitive noxious stimuli cause cAMP to increase its normal rate of activation of protein kinases involved in the phosphorylation of proteins that regulate gene transcription. The outcome is increased production of proteins (including enzymes) required for transmitter synthesis and of other proteins for construction of additional channels and synaptic cytoskeletons. Repetitive harmless stimuli merely reduce the rate of transmitter synthesis and release.
Gene transcription effects are especially important for forming long-term memories ( Chapter 34 ).
Transmitters and modulators
Several criteria should be fulfilled for a substance to be accepted as a neurotransmitter.
- •
The substance must be present within neurons, together with the molecules, including enzymes, required to synthesise it.
- •
The substance must be released following depolarisation of the nerve endings that contain it, and this release must be induced by the entry of Ca 2 + .
- •
The postsynaptic membrane must contain specific receptors that will modify the membrane potential of the target neuron.
- •
The isolated substance must exert the same effect when applied to a target neuron exogenously (microiontophoresis) .
- •
Specific antagonist molecules, whether delivered through the circulation or by iontophoresis, must block the effect of the putative transmitter.
- •
The physiologic mode of termination of the transmitter effect must be identified, whether it is by enzymatic degradation or by active transport into the parent neuron or adjacent neuroglial cells.
Many transmitters limit their own rate of release by negative feedback activation of autoreceptors in the presynaptic membrane, which inhibit further release. Ideally, the existence of specific inhibitory autoreceptors should be established.
The term neuromodulator (L. modulare, to regulate) has been subject to several interpretations. The most satisfactory appears to derive from the terms amplitude modulation and frequency modulation in electrical engineering, signifying superimposition of one wave or signal onto another. Figure 8.6 represents a sympathetic and a parasympathetic nerve ending, close to a pacemaker cell (modified cardiac myocyte). This neighbourly arrangement of nerve endings is common in the heart and allows the respective transmitters to modulate each other’s activity. The sympathetic nerve ending liberates norepinephrine (noradrenaline), which has a stimulatory effect. The three modulators shown exert their effects via second messenger systems.
The figure caption also refers to autoreceptors and heteroreceptors . Receptors for a particular transmitter that often occur in the presynaptic and postsynaptic membranes are called autoreceptors . These are activated by high transmitter concentration in the synaptic cleft, and they have a negative feedback effect, inhibiting further transmitter release from the synaptic bouton. Heteroreceptors occupy the plasma membrane of neurons that do not liberate the specific transmitter. In the example shown, activity at sympathetic nerve endings is accompanied by inhibition of parasympathetic activity through heteroreceptors located on parasympathetic nerve endings.
Fate of neurotransmitters
The ultimate fate of transmitters released into synaptic clefts is highly variable. Some transmitters are inactivated within the cleft, some diffuse away into the cerebrospinal fluid via the extracellular fluid, and some are recycled either by direct uptake or indirectly via glial cells.
The principal transmitters and modulators are shown in Table 8.2 . Respective receptor types are listed in Table 8.3 .
| Type | Example(s) |
|---|---|
| Amino acids | Glutamate |
| γ-Aminobutyric acid (GABA) | |
| Glycine | |
| Biogenic amines | Acetylcholine |
| Catecholamines (dopamine, norepinephrine [noradrenaline], epinephrine [adrenaline]) | |
| Histamine | |
| Monoamines | |
| Serotonin | |
| Neuropeptides | Endorphin |
| Enkephalin | |
| Substance P | |
| Vasoactive intestinal polypeptide | |
| Many others | |
| Adenosine | — |
| Gaseous | Nitric oxide |
* The five monoamines contain a single amine group. Catecholamines also contain a catechol nucleus.
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