Guide Glutamate and gaba receptors and transporters: structure, function and pharmacology

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Table of contents

To understand this, we need to consider another parameter, namely the permeability of the membrane for each ion. Pure phospholipid membranes are essentially impermeable for salt ions; therefore, in cell membranes, ion permeabilities are determined by specific transport proteins, the ion channels. Ion channels that open and close and thereby cause ion permeabilities to change are at the heart of cell excitation.

Some ion channels are continuously open, but most open transiently and then close again. Within this latter group, ligand-gated channels open in response to binding of a chemical agonist, while voltage-gated channels respond to changes in the membrane potential. Some channels may respond to both ligands and voltages. Yet others respond to changes in temperature or membrane distension; such channels are significant in sensing heat and pressure. Many channels are very specific for individual ion species, as shown in this illustration; this applies to the major voltage-gated channels that control the action potential.

Other channels have broader selectivity; for example, the nicotinic acetylcholine receptor slide 6. In this slide, P represents the ion-specific membrane permeabilities that are explained in the next slide.

Glutamate and GABA Receptors and Transporters: Structure, Function and Pharmacology

In addition to the terms known from the Nernst equation, it introduces the permeability P , a scaling factor that weights each ion for its rate of diffusion across the membrane, relative to that of the other ions. If channels open for a specific ion, its permeability goes up. This increases the weight of this ion in the Goldman equation, and thus pulls the overall membrane potential toward its own Nernst equilibrium potential. However, all that is needed to flip the membrane potential from its negative-inside resting state to a positive-inside value is a forceful opening of sodium or calcium channels.

On the other hand, opening of chloride channels or of additional potassium channels will drive the membrane potential back down toward the resting state or below. As stated above, such transient reversals of the membrane potential are referred to as action potentials. In nerve and skeletal muscle cells, an action potential lasts only 1—3 milliseconds, and the absolute number of ions that cross the membrane during this short time interval is very low.

The one important exception from this rule is calcium. Its intracellular concentration is so low see slide 6. The increased intracellular calcium level will cause activation of calmodulin and other calcium-binding proteins. Therefore, the opening of calcium channels constitutes both a physical and a biochemical signal. Calcium channels are important in nerve cells, and they are particularly prominent in heart and smooth muscle cells, where they replace sodium channels as the primary drivers of membrane potential reversal, or depolarization.

Voltage-gated cation channels are crucial in triggering, sustaining and propagating action potentials. The picture on the left shows a side view. The gray rectangle delineates the membrane-embedded portion. A large part of the channel protein protrudes into the cytosol. The channel is composed of four identical subunits; one is shown in blue, the one opposite to it in yellow, and the other two in light gray. The conformationally flexible N-terminal inactivation domain that is located in the cytosolic portion see below is missing from this structure.

The panel on the right shows a view from the extracellular side onto the membrane-embedded domain of the channel. This domain consists of an inner layer, which contains the selectivity filter, and an outer layer that mediates voltage-dependent channel opening.

In each of the four subunits, an arginine-rich helix that forms the voltage sensor is rendered in a darker shade. A potassium ion inside the central channel pore is shown as a green ball. Structure rendered from 2r9r. Each of the four subunits contributes one backbone segment, but for clarity only two segments are shown in the side view.

GABAergic system

The selectivity filters found in sodium and calcium channels work according to the same principle, although they differ in diameter and architectural detail. In each case, the filter fits the ion like a glove. Ions that are too large are simply excluded; those that are too small are rejected because they cannot bind avidly to the filter, and therefore cannot compensate the energetic cost of their dehydration. As stated above, all voltage-gated channels have the same general structure as the K V channel, so we will now see how those structural features operate in practice.

When the membrane potential in the vicinity of a sodium channel is reversed by a spreading action potential, the membrane-embedded voltage sensor moves outward, which decompresses the inner layer and opens the channel. After the channel has been open for a short time, 32 a separate inactivation gate, which is flexibly attached to the cytosolic portion of the channel and also carries a positive net charge—and which, as stated, is missing from the K V channel structure shown in slide 6. The channel is now inactivated, in spite of the continued depolarized state of the membrane.

Before the channel becomes ready for opening again, both gates must revert to their initial conformations, which happens only after the membrane has been repolarized.


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This slide illustrates the interplay of Na V and K V channels in shaping the action potential. Both channels open in response to depolarization. The Na V channels open and inactivate faster and therefore dominate the early depolarization phase of the action potential. The slower response of the K V channels dominates the later phase and causes a transient hyperpolarization of the membrane. As long as the composition of the channel population remains the same, the shape and amplitude of each action potential will also be the same.

The interplay between sodium and potassium channel controls the action potentials in nerve and muscle fibers, which are of short duration and often occur with high repetition rates. In contrast, action potentials in the heart last much longer and occur with lower frequency, and their control involves voltage-gated channels for calcium in addition to those for sodium and potassium.

The heart contains two types of excitable cells: those in the excitation-conduction system generate action potentials spontaneously and periodically, whereas the worker muscle cells stay put until they are ordered otherwise, much like the muscle fibers in skeletal muscle. The latter is true at least in a healthy heart; however, in certain forms of arrhythmia, worker cells create havoc by firing autonomously, and drug treatment will then aim to silence them again.

The various parts of the excitation-conduction system are hierarchically organized. In a healthy heart, action potentials are generated in the sino-atrial node, which is the topmost center of the excitation-conduction system. From there, the action potentials travel to the atrioventricular node and then spread across the remainder of the system and to the worker cells. In the sinoatrial node, T type Ca V channels open slowly and spontaneously at the resting potential, causing a gradual depolarization.

Once this depolarization reaches the firing level of the faster and more abundant L type Ca V channels, these open rapidly and trigger an action potential. In the worker muscle cells, the action potential is initiated by Na V channels and sustained for the duration of the contraction through Ca V channels. Repolarization is mediated by L channel inactivation and by opening of some fairly tardily responding K V channels.

Among these, the so-called hERG channels have a prominent role as drug targets and antitargets see section 6. One of the allures that ion channels hold for many researchers is the ease and detail with which the behavior of individual channel molecules can be studied. Here, we take a brief look at how this is done.


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Purified channel molecules, typically solubilized with some non-denaturing detergent, are introduced into one reservoir. Membrane proteins prepared in this way tend to spontaneously insert again into lipid bilayers when offered the opportunity; the right amount of protein sample that will cause just one channel molecule to find and insert into the membrane patch is determined by trial and error. Electrodes are inserted into the buffer reservoirs on both sides of the bilayer.

Voltage is applied, and the opening and closing of the channel can be observed, typically in the form of discrete jumps of constant magnitude that is proportional to the conductivity of the channel molecule. In the patch clamp technique, the channel is observed in its natural environment within the cell membrane; therefore, interactions with regulatory proteins or other effectors are preserved. Isolated observation of a single channel, or of a small number of channels, is accomplished by gently lowering a glass micro-pipette onto the cell surface, such that it forms a seal with the cell membrane.

All current through the pipette must then flow through the membrane patch delineated by the pipette aperture, and through any channels this patch happens to contain. Patch clamp experiments can be performed either in whole-cell mode or in excised-patch mode. In whole-cell mode, the current has to pass the membrane twice in order to close the circuit: once across the sealed patch, and once across the remainder of the cell surface.

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However, the latter contains very many channel molecules working in parallel, causing negligible ohmic resistance; therefore, the current is controlled almost exclusively by the channels in the patch. In excised-patch mode, the pipette is withdrawn after seal formation; the cell membrane ruptures, with the pipette holding on to the sealed patch of membrane.

This makes it possible to experimentally vary the buffer milieu on both the extracellular side and the intracellular side of the membrane. Channels of different specificities will usually be present in the membrane patch, and in order to selectively observe one species, some others may need to be suppressed, either through addition of specific inhibitors, or through elimination of their specific substrate ions from the buffer.

Sodium channels play a crucial role in the propagation of action potentials, and thus they are a good target when inhibition of nerve conduction is desired, as it is in local anesthesia. In addition, inhibitors of sodium channels are also used in several other situations that require neural excitability to be dampened. Channel-blocking drugs may cause either fast or slow blocks.

ABBREVIATIONS

A fast block occurs when a drug reversibly binds within the channel lumen and obstructs it. A slow block is observed when a drug binds to the inactivated state of the channel and delays its reactivation. Both fast and slow blocks may be use-dependent , which means that the channel needs to be activated in order to allow the drugs to enter and apply the block. The drug lidocaine is used for local anesthesia and in the treatment of certain types of cardiac arrhythmias. It causes both slow and fast block at the Na V channel.

The model compounds diethylamine and phenol resemble parts of the lidocaine molecule; as we will see in the next slide, they also mimic partial activities of it. Cocaine also blocks sodium channels and can be used for local anesthesia, 37 but it is no longer used in this application. This activity of cocaine is unrelated to its psychotropic effect that is caused in dopaminergic synapses slide 6. This slide shows a series of single channel recordings on Na V channels in planar lipid bilayers. The channels were biased towards the open state with batrachotoxin see next slide.

Individual binding and dissociation events occur faster than can be resolved by the recording electronics, which therefore averages them out and reports an apparent decrease in the conductance. Such behavior constitutes a fast block. In contrast to diethylamine, phenol measurably extends the time intervals of channel inactivity but does not alter the observed conductivity of the open state. This effect represents a slow block. Thus, it appears that diethylamine and phenol respectively account for the dual fast and slow block that was reported previously for lidocaine.

Figure adapted from [ 42 ]. Batrachotoxin interacts with the channel from within the lipid bilayer and activates it. It has no therapeutic application but is useful in experimental studies on Na V channels, such as the one illustrated in the preceding slide. All other molecules shown here are Na V channel blockers. Tetrodotoxin is the poison found in pufferfish. Mexiletine is a more metabolically stable analogue of lidocaine; it can be applied orally and is used in some forms of cardiac arrhythmia, as is quinidine. Carbamazepine is used to treat epilepsy and some other neurological and psychiatric diseases.

Phenytoin is also used in epilepsy.