Long established as the preeminent source in its field, the eagerly anticipated fifth edition of Dr Stahl's essential textbook of psychopharmacology is here! With its use of icons and figures that form Dr Stahl's unique 'visual language', the book is the single most readable source of information on disease and drug mechanisms for all students and mental health professionals seeking to understand and utilize current therapeutics, and to anticipate the future for novel medications. Every aspect of the book has been updated, with the clarity of explanation that only Dr Stahl can bring.
Ion Channels as Targets of Psychopharmacological Drug Action
Many important psychopharmacological drugs target ion channels. The role of ion channels as important regulators of synaptic neurotransmission has been covered in Chapter 1. Here we discuss how targeting these molecular sites causes alterations in synaptic neurotransmission that are linked in turn to the therapeutic actions of various psychotropic drugs. Specifically, we will cover ligand-gated ion channels and voltage-sensitive ion channels as targets of psychopharmacological drug action.
The terms ligand-gated ion channels, ionotropic receptors, and ion-channel-linked receptors are in fact different terms for the same receptor/ion-channel complex. Ions normally cannot penetrate membranes because of their charge. In order to selectively control access of ions into and out of neurons, their membranes are decorated with all sorts of ion channels. The most important ion channels in psychopharmacology regulate calcium, sodium, chloride, and potassium. Many can be modified by various drugs, and this will be discussed throughout this chapter.
There are two major classes of ion channels, and each class has several names. One class of ion channels is opened by neurotransmitters and goes by the names ligand-gated ion channels, ionotropic receptors, and ion-channel-linked receptors. These channels and their associated receptors will be discussed next. The other major class of ion channel is opened by the charge or voltage across the membrane and is called either a voltage-gated or a voltage-sensitive ion channel, and these will be discussed later in this chapter.
Ion channels that are opened and closed by actions of neurotransmitter ligands at receptors acting as gatekeepers are shown conceptually in Figure 3-1. When a neurotransmitter binds to a gatekeeper receptor on an ion channel, that neurotransmitter causes a conformational change in the receptor that opens the ion channel (Figure 3-1A). A neurotransmitter, drug, or hormone that binds to a receptor is sometimes called a ligand (literally, “tying”). Thus, ion channels linked to receptors that regulate their opening and closing are often called ligand-gated ion channels. Since these ion channels are also receptors, they are also sometimes also called ionotropic receptors or ion-channel linked receptors. These terms will be used interchangeably with ligand-gated ion channels here.
Numerous drugs act at many sites around such receptor/ion-channel complexes, leading to a wide variety of modifications of receptor/ion-channel actions. These modifications not only immediately alter the flow of ions through the channels, but with a delay can also change the downstream events that result from transduction of the signal that begins at these receptors. The downstream actions have been extensively discussed in Chapter 1 and include both activation and inactivation of phosphoproteins, shifting the activity of enzymes, the sensitivity of receptors, and the conductivity of ion channels. Other downstream actions include changes in gene expression and thus changes in which proteins are synthesized and which functions are amplified. Such functions can range from synaptogenesis, to receptor and enzyme synthesis, to communication with downstream neurons innervated by the neuron with the ionotropic receptor, and many more. The reader should have a good command of the function of signal transduction pathways described in Chapter 1 in order to understand how drugs acting at ligand-gated ion channels modify the signal transduction that arises from these receptors.
Drug-induced modifications in signal transduction from ionotropic (sometimes called ionotrophic) receptors can have profound actions on psychiatric symptoms. About a fifth of psychotropic drugs currently utilized in clinical practice, including many drugs for the treatment of anxiety and insomnia such as the benzodiazepines, are known to act at these receptors. Because ionotropic receptors immediately change the flow of ions, drugs that act on these receptors can have an almost immediate effect, which is why many drugs for anxiety and for sleep that act at these receptors may have immediate clinical onset. This is in contrast to the actions of many drugs at G-protein-linked receptors described in Chapter 2, some of which have clinical effects – such as actions on mood – that may occur with a delay necessitated by awaiting initiation of changes in cellular functions activated through the signal transduction cascade. Here we will describe how various drugs stimulate or block various molecular sites around the receptor/ion-channel complex. Throughout the textbook we will show how specific drugs acting at specific ionotropic receptors have specific actions on specific psychiatric disorders.
Are ligand-gated ion channels receptors or ion channels? The answer is “yes” – ligand-gated ion channels are both a type of receptor and they also form an ion channel. That is why they are called not only a channel (ligand-gated ion channel) but also a receptor (ionotropic receptor and ion-channel-linked receptor). These terms try to capture the dual function of these ion channels/receptors and may explain why there is more than one term for this receptor/ion-channel complex.
Ligand-gated ion channels are comprised of several long strings of amino acids assembled as subunits around an ion channel. Decorated on these subunits are also multiple binding sites for everything from neurotransmitters to ions to drugs. That is, these complex proteins have several sites where some ions travel through a channel and others also bind to the channel; where one neurotransmitter or even two cotransmitters act at separate and distinct binding sites; where numerous allosteric modulators – i.e., natural substances or drugs that bind to a site different than where the neurotransmitter binds – increase or decrease the sensitivity of channel opening.
Many ligand-gated ion channels are assembled from five protein subunits, and that is why they are called pentameric. The subunits for pentameric subtypes of ligand-gated ion channels each have four transmembrane regions (Figure 3-2A). These membrane proteins go in and out of the membrane four times (Figure 3-2A). When five copies of these subunits are selected (Figure 3-2B), they come together in space to form a fully functional pentameric receptor with the ion channel in the middle (Figure 3-2C). The receptor sites are in various locations on each of the subunits; some binding sites are in the channel, but many are present at different locations outside the channel. This pentameric structure is typical for GABAA receptors, nicotinic cholinergic receptors, serotonin 5HT3 receptors, and certain glycine receptors (Table 3-1). Drugs that act directly on pentameric ligand-gated ion channels are listed in Table 3-2.
|Four transmembrane regions Five subunits|
|Acetylcholine||Nicotinic receptors(e.g. α7 nicotinic receptors; α4β2 nicotinic receptors)|
|GABA||GABAA receptors (e.g. α1 subunits; γ subunits; δ subunits)|
|Glycine||Strychnine-sensitive glycine receptors|
|Neurotransmitter||Ligand-gated ion channel receptor subtype directly targeted||Pharmacological action||Drug class||Therapeutic action|
|Acetylcholine||Alpha4 Beta2 nicotinic||Partial agonist||Nicotinic receptor partial agonist (NRPA)(varenicline)||Smoking cessation|
|GABA||GABAA benzodiazepine receptors||Full agonist, phasic inhibition||Benzodiazepines||Anxiolytic|
|GABAA non-benzodiazepine PAM sites||Full agonist, phasic inhibition||“Z DRUGS”/hypnotics (zolpidem, zaleplon, zopiclone, eszopiclone)||Improves insomnia|
|GABAA neurosteroid sites (benzodiazepine insensitive)||Full agonist, tonic inhibition||Neuroactive steroids (allopregnanolone)||Post-partum depression Rapid-acting antidepressant Anesthetic|
|Glutamate||NMDANAM channel sites/Mg++ sites||Antagonist||NMDA glutamate antagonist (memantine)||Procognitive in Alzheimer’s disease|
|NMDA open-channel sites||Antagonist||PCP/phencyclidine Ketamine Dextromethorphan Dextromethadone||Dissociative hallucinogen Anesthetic Pseudobulbar affect Agitation in Alzheimer’s disease Rapid-acting antidepressant Treatment-resistant depression|
|Serotonin||5HT3||Antagonist||Mirtazapine||Procognitive Vortioxetine Antidepressant|
|5HT3||Antagonist||Anti-emetic||Reduce chemotherapy-induced emesis|
PAM, positive allosteric modulator; NAM, negative allosteric modulator; NMDA, N-methyl-D-aspartate; Mg, magnesium.
If this structure were not complicated enough, pentameric ionotropic receptors actually have many different subtypes. Subtypes of pentameric ionotropic receptors are defined based upon which forms of each of the five subunits are chosen for assembly into a fully constituted receptor. That is, there are several subtypes for each of the four transmembrane subunits, making it possible to piece together several different constellations of fully constituted receptors. Although the natural neurotransmitter binds to every subtype of ionotropic receptor, some drugs used in clinical practice, and many more in clinical trials, are able to bind selectively to one or more of these subtypes, but not to others. This may have functional and clinical consequences. Specific receptor subtypes and the specific drugs that bind to them selectively are discussed in chapters that cover their specific clinical use.
Ionotropic glutamate receptors have a different structure from the pentameric ionotropic receptors just discussed. The ligand-gated ion channels for glutamate are comprised of subunits that have three full transmembrane regions and a fourth re-entrant loop (Figure 3-3A), rather than four full transmembrane regions as shown in Figure 3-2A. When four copies of these subunits are selected (Figure 3-3B), they come together in space to form a fully functional ion channel in the middle with the four re-entrant loops lining the ion channel (Figure 3-3C). Thus, tetrameric subtypes of ion channels (Figure 3-3) are analogous to pentameric subtypes of ion channels (Figure 3-2A), but just have four subunits rather than five. Receptor sites are in various locations on each of the subunits; some binding sites are in the channel, but many are present at different locations outside the channel.
This tetrameric structure is typical of the ionotropic glutamate receptors known as AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid), kainate, and NMDA (N-methyl-D-aspartate) subtypes (Table 3-3). Drugs that act directly at tetrameric ionotropic glutamate receptors are listed in Table 3-2. Receptor subtypes for glutamate according to the selective agonist acting at that receptor as well as the specific molecular subunits that comprise that subtype are listed in Table 3-3. Subtype selective drugs for ionotropic glutamate receptors are under investigation but not currently used in clinical practice.
|Three transmembrane regions and one re-entrant loop Four subunits|
|Glutamate||AMPA (e.g. GluR1–4 subunits)|
|KAINATE (e.g. GluR5–7, KA1–2 subunits)|
|NMDA (e.g. NMDAR1, NMDAR2A–D, NMDAR3A subunits)|
AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; NMDA, N-methyl-D-aspartate.
The concept of an agonist spectrum for G-protein-linked receptors discussed extensively in Chapter 2 can also be applied to ligand-gated ion channels (Figure 3-4). Thus, full agonists change the conformation of the receptor to open the ion channel the maximal frequency allowed by that binding site (Figure 3-5). This then triggers the maximal amount of downstream signal transduction possible to be mediated by this binding site. The ion channel can open to an even greater extent (i.e., more frequently) than with a full agonist alone, but this requires the help of a second receptor site, that of a positive allosteric modulator (PAM) as will be shown later.
Antagonists stabilize the receptor in the resting state (Figure 3-6B), which is the same as the state of the receptor in the absence of agonist (Figure 3-6A). Since there is no difference between the presence and absence of the antagonist, the antagonist is said to be neutral or silent. The resting state is not a fully closed ion channel, so there is some degree of ion flow through the channel even in the absence of agonist (Figure 3-6A) and even in the presence of antagonist (Figure 3-6B). This is due to occasional and infrequent opening of the channel even when an agonist is not present and even when an antagonist is present. This is called constitutive activity and is also discussed in Chapter 2 for G-protein-linked receptors. Antagonists of ion-channel-linked receptors reverse the action of agonists (Figure 3-7) and bring the receptor conformation back to the resting baseline state, but do not block any constitutive activity.
Partial agonists produce a change in receptor conformation such that the ion channel opens to a greater extent and more frequently than in its resting state but less than in the presence of a full agonist (Figures 3-8 and 3-9). An antagonist reverses a partial agonist, just like it reverses a full agonist, returning the receptor to its resting state (Figure 3-10). Partial agonists thus produce ion flow and downstream signal transduction that is something more than the resting state in the absence of agonist, yet something less than a full agonist. Just as is the case for G-protein-linked receptors, depending upon how close this partial agonist is to a full agonist or to a silent antagonist on the agonist spectrum will determine the impact of a partial agonist on downstream signal transduction events.
The ideal therapeutic agent should have ion flow and signal transduction that is not too hot, yet not too cold, but just right, called the “Goldilocks” solution in Chapter 2, a concept that can apply here to ligand-gated ion channels as well. Such an ideal state may vary from one clinical situation to another, depending upon the balance between full agonism and silent antagonism that is desired. In cases where there is unstable neurotransmission throughout the brain, finding such a balance may stabilize receptor output somewhere between too much and too little downstream action. For this reason, partial agonists are also called “stabilizers,” since they have the theoretical capacity to find the stable solution between the extremes of too much full agonist action and no agonist action at all (Figure 3-9).
Just as is the case for G-protein-linked receptors, partial agonists at ligand-gated ion channels can appear as net agonists, or as net antagonists, depending upon the amount of naturally occurring full agonist neurotransmitter which is present. Thus, when a full agonist neurotransmitter is absent, a partial agonist will be a net agonist (Figure 3-9). That is, from the resting state, a partial agonist initiates somewhat of an increase in the ion flow and downstream signal transduction cascade from the ion-channel-linked receptor. However, when full agonist neurotransmitter agonist is present, the same partial agonist will become a net antagonist (Figure 3-9). That is, it will decrease the level of full signal output to a lesser level, but not to zero. Thus, a partial agonist can simultaneously boost deficient neurotransmitter activity yet block excessive neurotransmitter activity, another reason that partial agonists are called stabilizers. An agonist and an antagonist in the same molecule acting at ligand-gated ion channels is quite an interesting new dimension to therapeutics. This concept has led to proposals that partial agonists could treat not only states which are theoretically deficient in full agonist, but also states that are theoretically in excess of full agonist. As mentioned in the discussion of G-protein-linked receptors in Chapter 2, a partial agonist at ligand-gated ion channels could also theoretically treat states that are mixtures of both excessive and deficient neurotransmitter activity. Partial agonists at ligand-gated ion channels are just beginning to enter into use in clinical practice (Table 3-2), and several more are in clinical development.
Inverse agonists at ligand-gated ion channels are different from simple antagonists, and are neither neutral nor silent. Inverse agonists are explained in Chapter 2 in relationship to G-protein-linked receptors. Inverse agonists at ligand-gated ion channels are thought to produce a conformational change in these receptors that first closes the channel and then stabilizes it in an inactive form (Figure 3-11). Thus, this inactive conformation (Figure 3-11B) produces a functional reduction in ion flow and in consequent signal transduction compared to the resting state (Figure 3-11A) that is even less than that produced when there is either no agonist present or when a silent antagonist is present. Antagonists reverse this inactive state caused by inverse agonists, returning the channel to the resting state (Figure 3-12).
In many ways, therefore, an inverse agonist does the opposite of an agonist. If an agonist increases signal transduction from baseline, an inverse agonist decreases it, even below baseline levels. Also, in contrast to antagonists, which stabilize the resting state, inverse agonists stabilize an inactivated state (Figures 3-11 and 3-13). It is not yet clear if the inactivated state of the inverse agonist can be distinguished clinically from the resting state of the silent antagonist at ionotropic receptors. In the meantime, inverse agonists remain an interesting pharmacological concept.
In summary, ion-channel-linked receptors act along an agonist spectrum, and drugs have been described that can produce conformational changes in these receptors to create any state from full agonist, to partial agonist, to silent antagonist, to inverse agonist (Figure 3-4). When one considers the spectrum of signal transduction along this spectrum, it is easy to understand why agents at each point along the agonist spectrum differ so much from each other, and why their clinical actions are so different.
There are even more states of ligand-gated ion channels than those determined by the agonist spectrum discussed above and shown in Figures 3-4 through 3-13. The states discussed so far are those that occur predominantly with acute administration of agents that work across the agonist spectrum. These range from the maximal opening of the ion channel from conformational changes caused by a full agonist to the maximal closing of the ion channel caused by an inverse agonist. Such changes in conformation caused by the acute action of agents across this spectrum are subject to change over time since these receptors have the capacity to adapt, particularly when there is chronic or excessive exposure to such agents.
We have already discussed the resting state, the open state, and the closed state shown in Figure 3-14. The best-known adaptive states are those of desensitization and inactivation, also shown in Figure 3-14. We have also briefly discussed inactivation as a state that can be caused by acute administration of an inverse agonist, beginning with a rapid conformational change in the ion channel that first closes it, but over time stabilizes the channel in an inactive conformation that can relatively quickly be reversed by an antagonist, which then restabilizes the ion channel in the resting state (Figures 3-11 through 3-13).
Desensitization is yet another state of the ligand-gated ion channel shown in Figure 3-14. Ion-channel-linked receptor desensitization can be caused by prolonged exposure to agonists, and may be a way for receptors to protect themselves from overstimulation. An agonist acting at a ligand-gated ion channel first induces a change in receptor conformation that opens the channel, but with the continuous presence of the agonist, over time leads to another conformational change where the receptor essentially stops responding to the agonist even though the agonist is still present. This receptor is then considered to be desensitized (Figures 3-14 and 3-15). This state of desensitization can at first be reversed relatively quickly by removal of the agonist (Figure 3-15). However, if the agonist stays much longer, on the order of hours, the receptor converts from a state of simple desensitization to one of inactivation (Figure 3-15). This state does not reverse simply upon removal of the agonist, since it also takes hours in the absence of agonist to revert back to the resting state where the receptor is again sensitive to new exposure to agonist (Figure 3-15).
The state of inactivation may be best characterized for nicotinic cholinergic receptors, ligand-gated ion channels that are normally responsive to the endogenous neurotransmitter acetylcholine. Acetylcholine is quickly hydrolyzed by an abundance of the enzyme acetylcholinesterase, so it rarely gets the chance to desensitize and inactivate its nicotinic receptors. However, the drug nicotine is not hydrolyzed by acetylcholinesterase, and is famous for stimulating nicotinic cholinergic receptors so profoundly and so enduringly that the receptors are not only rapidly desensitized in about the time it takes to smoke a single cigarette, but enduringly inactivated for about the time most smokers take between cigarettes. Ever wonder why cigarettes are the length they are and why most smokers smoke about a pack a day (20 cigarettes) in about 16 waking hours? It all has to do with adjusting the dosing of nicotine to the nature of receptor action of nicotinic receptors described here. Addiction to nicotine and other substances is described in more detail in Chapter 13 on impulsivity and substance abuse. These transitions among various receptor states induced by agonists are shown in Figure 3-15.
Ligand-gated ion channels are regulated by more than the neurotransmitter(s) that bind to them. That is, there are other molecules that are not neurotransmitters but can bind to the receptor/ion channel complex at different sites from where neurotransmitter(s) bind. These sites are called allosteric (literally, “other site”) and ligands that bind there are called allosteric modulators. These ligands are modulators rather than neurotransmitters because they have little or no activity on their own in the absence of the neurotransmitter. Allosteric modulators thus only work in the presence of the neurotransmitter.
There are two forms of allosteric modulators – those that boost what the neurotransmitter does and are thus called positive allosteric modulators (PAMs), and those that block what the neurotransmitter does and are thus called negative allosteric modulators (NAMs).
Specifically, when PAMs or NAMs bind to their allosteric sites while the neurotransmitter is not binding to its site, the PAM and the NAM do nothing. However, when a PAM binds to its allosteric site while the neurotransmitter is sitting in its site, the PAM causes conformational changes in the ligand-gated ion channel that open the channel even further and more frequently than happens with a full agonist by itself (Figure 3-16). That is why the PAM is called “positive.” Good examples of PAMs are benzodiazepines. These ligands boost the action of GABA (γ-aminobutyric acid) at GABAA types of ligand-gated chloride ion channels. GABA binding to GABAA sites increases chloride ion flux by opening the ion channel, and benzodiazepines acting as agonists at benzodiazepine receptors elsewhere on the GABAA receptor complex cause the effect of GABA to be amplified in terms of chloride ion flux by opening the ion channel to a greater degree or more frequently. Clinically, this is exhibited as reducing anxiety, inducing sleep, blocking convulsions, blocking short-term memory, and relaxing muscles. In this example, benzodiazepines are acting as full agonists at the PAM site.
On the other hand, when a NAM binds to its allosteric site while the neurotransmitter resides at its agonist binding site, the NAM causes conformational changes in the ligand-gated ion channel that block or reduce the actions that normally occur when the neurotransmitter acts alone (Figure 3-17). That is why the NAM is called “negative.” One example of a NAM is a benzodiazepine inverse agonist. Although these are only experimental, as expected, they have the opposite actions of benzodiazepine full agonists and thus diminish chloride conductance through the ion channel so much that they cause panic attacks, seizures, and some improvement in memory – the opposite clinical effects of a benzodiazepine full agonist. Thus, the same allosteric site can either have NAM or PAM actions, depending upon whether the ligand is a full agonist or an inverse agonist. NAMs for NMDA receptors include phencyclidine (PCP, also called “angel dust”) and its structurally related anesthetic agent ketamine, also used as a treatment for resistant depression and suicidal thoughts. These agents bind to a site inside the calcium channel, but can get into the channel to block it only when the channel is open. When either PCP or ketamine bind to their NAM site, they prevent glutamate/glycine cotransmission from opening the channel.