Ion channels as targets of psychopharmacological drug action
Many important psychopharmacological drugs target ion channels. The roles of ion channels
as important regulators of synaptic neurotransmission were 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 cover ligand-gated ion channels and voltage-sensitive ion
channels as targets of psychopharmacological drug action.
Ligand-gated ion channels as targets of psychopharmacological drug action
Ligand-gated ion channels, ionotropic receptors, and ion-channel-linked receptors:
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-sensitive or a voltage-gated ion channel; 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 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 anxiolytics and hypnotics 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 antidepressant actions – 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.
Ligand-gated ion channels: structure and function
Are ligand-gated ion channels receptors or ion channels? The answer is “yes” – ligand-gated
ion channels are 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 or ion-channel-linked receptor). These terms try to capture the
dual function of these ion channels/receptors.
Ligand-gated ion channels comprise several long strings of amino acids assembled as
subunits around an ion channel. Decorating 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; 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 glycine receptors (Table 3-1). Drugs that act directly on pentameric ligand-gated ion channels are listed in Table 3-2.
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
Table 3-1 Pentameric ligand-gated ion channels
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.
Table 3-2 Key ligand-gated ion channels directly targeted by psychotropic drugs
Ionotropic glutamate receptors have a different structure from the pentameric ionotropic
receptors just discussed. The ligand-gated ion channels for glutamate comprise 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 3-2), but have just 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) 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.
The agonist spectrum
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 amount
and 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, or PAM, as will
be shown later.
Table 3-3 Tetrameric ligand-gated ion channels
Antagonists stabilize the receptor in the resting state, which is the same as the state of the
receptor in the absence of agonist (Figure 3-6). 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 as 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, 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
The ideal therapeutic agent in some cases may need to 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 that 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 is present, the same partial
agonist will become a net antagonist (Figure 3-9): 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 that 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 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 relation 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 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.
Different states of ligand-gated ion channels
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 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, because 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 be relatively quickly 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 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, then 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 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, but enduringly inactivated,
requiring hours in the absence of agonist to get back to the resting state. These
transitions among various receptor states induced by agonists are shown in Figure 3-15
. Desensitization of nicotinic receptors is discussed in further detail in Chapter 14
Allosteric modulation: PAMs and NAMs
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
that 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
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 at 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 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 anxiolytic, hypnotic, anticonvulsant, amnestic, and muscle relaxant
actions. 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
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 have either 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. These agents bind to a site in 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