Transmitters and receptors

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8 Transmitters and receptors

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) disposed in hexagonal format 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 having a common action. An example is the inspiratory center 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 liberation (Table 8.1 and Figure 8.2)

At 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, myriads of voltage-gated calcium channels located in the presynaptic membrane are opened, leading to instant flooding of the active zone with Ca2+ ions. These ions cause contraction of actin filaments to bring the nearest vesicles into direct contact with the presynaptic membrane.

Table 8.1 Some named proteins involved in transmitter transport and vesicle recycling

Named protein Function
Actin Brings vesicle into contact with presynaptic membrane
Synaptophysin Creates the membrane fusion pore
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

When the vesicle protein synaptophysin contacts the vesicle membrane, it becomes embedded in it and hollows out to create a fusion pore through which the vesicle discharges its contents into the synaptic cleft. The act of expulsion appears to be a function of another vesicle protein, calmodulin, activated by Ca2+ ions. These and other local protein responses to calcium entry are extremely rapid, the time elapsing between calcium entry and transmitter expulsion being 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.

Target cell receptor binding

Transmitter molecules bind with receptor protein molecules in the postsynaptic membrane. The two great categories of receptor are known as ionotropic and metabotropic. Each category contains some receptors whose activation leads to opening of ion pores and others whose activation leads to closure.

Ionotropic receptors

Ionotropic receptors are characterized by the presence of an ion channel within each receptor macromolecule (Figure 8.2). The transmitter binds with its specific receptor facing the synaptic cleft, causing it to change its conformation so as to open or close its ion pore. Ionotropic receptor channels are said to be transmitter-gated, or ligand-gated (from the Latin ligandum, ‘binding’), signifying their capacity to bind a transmitter molecule or a drug substitute.

In Figure 8.3A, the excitatory channel has been opened by the transmitter, causing a major influx of sodium and a minor efflux of potassium; the excitatory postsynaptic potential (EPSP) has depolarized the cell membrane almost to firing point. In Figure 8.3B, the membrane can be hyperpolarized only to −70 mV, the chloride equilibrium potential. A greater level of depolarization requires a second messenger system (see below).

Ionotropic receptors are called fast receptors on account of their immediate and 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 an intrinsic membrane protein devoid of an ion channel. Its function is initiated by one or other of two subunits (α subunit, β subunit) that detaches in response to transmitter activation 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. Their action on ion channels is usually indirect, via a second messenger system. However, some G proteins do not bind with nucleotides; instead, they activate ion channels directly (see later).

A G protein having a stimulatory effect is known as a Gs protein; a Gi protein is one with an inhibitory effect.

Three second messenger systems are well recognized.

Phosphoinositol system

In the example shown in Figure 8.5, activation of another kind of Gs protein alpha subunit causes the effector enzyme phospholipase C to split a membrane phospholipid (PIP2) into a pair of second messengers: diacylglycerol (DAG) and inositol phosphate (IP3). DAG activates protein kinase C, which initiates protein phosphorylation. IP3 diffuses into the cytosol, where it opens calcium-gated channels, mainly in nearby membranes of smooth endoplasmic reticulum. The Ca2+ ions activate certain calcium-dependent enzymes downstream, and may open calcium-gated K+ (outward) and Cl (inward) channels with excitatory effect.

Transmitters and Modulators

Several criteria should be fulfilled for a substance to be accepted as a neurotransmitter.

Many transmitters limit their own rate of release by negative feedback activation of autoreceptors in the presynaptic membrane, having the effect of inhibiting 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 neighborly 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 often occur in the presynaptic as well as in the postsynaptic membrane. They 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 the medium of 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 in Table 8.3.

Table 8.2 Main types of transmitters and modulators, with examples of eacha The neuropeptides are modulators

Type Example(s)
Amino acids Glutamate
γ-Aminobutyric acid (GABA)
Glycine
Biogenic amines Acetylcholine
Monoamines
Catecholamines (dopamine, norepinephrine [noradrenaline], epinephrine [adrenaline])
Serotonin
Histamine
Neuropeptides Vasoactive intestinal polypeptide
Substance P
Enkephalin
Endorphins
Many others
Adenosine
Gaseous Nitric oxide

a The five monoamines contain a single amine group. Catecholamines also contain a catechol nucleus.

Table 8.3 Receptor types activated by different neurotransmitters

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Ionotropic receptors Metabotropic receptors
Glutamate (AMPA/K) Glutamate (mGluR)
GABAA GABAA
Acetylcholine (nicotinic) Acetylcholine (muscarinic)
Glycine