Chapter 3: Ion Channels as Targets of Psychopharmacologic Drug Action
How targeting ion channels causes alterations in synaptic neurotransmission that are
linked to the therapeutic actions of various drugs
o Ligand-gated ion channels
o Voltage-sensitive ion channels
Ligand-gated Ion Channels as Targets of Psychopharmacological
Drug Action
Ligand-gated ion channels, ionotropic receptors and ion-channel-linked receptors
o Neurotransmitter binds to a gate-keeper receptor on an ion channel
This causes conformational change in the receptor that opens the ion channel
Neurotransmitter/drug/hormone ligand
Since ion channels are also receptors they are ionotropic receptors
o Fifth of psychotropic drugs act at these receptors
Treatment of anxiety and insomnia including benzodiazepines
Drugs that act on these receptors have an almost immediate effect
o Contrasted with G protein linked receptors which have a delay
d/t awaiting initiation of changes in cellular functions activated
through the signal transduction cascade.
Ligand Gated Ion Channels – Structure and Function
Comprised of several long strings of amino acids assembled as subunits around an ion
channel
o Multiple binding sites are on the subunits for everything from neurotransmitters to
drugs
Several sites where some ions travel through a channel and others also bind
to the channel
Allosteric modulators:
o Natural substances or drugs that bind to a site different than
where the neurotransmitter binds
o Can increase or decrease the sensitivity of channel opening
Pentameric Subtypes
o Assembled from five protein subunits pentameric
Each have four transmembrane regions
Some receptor sites are in the channel but also many different
locations outside of the channel
o This structure is typical for GABA receptors, nicotinic cholinergic
receptors, serotonin 5HT3 receptors and certain glycine
receptors
Acetylcholine nicotinic receptors
GABA GABA receptors (3 different subunits)
Glycine Strychnine-sensitive glycine receptors
Serotonin 5HT3 receptors
Tetrameric Subtypes
o Ligand-gated ion channels for glutamate
Comprised of subunits that have three full transmembrane regions and a
fourth re-entrant loop
Rather than four transmembrane regions
When four copies of these subunits are selected, they come together
, o Form a fully functional ion channel in the middle with the four re-
entrant loops lining the ion channel
Analogous to pentameric subtypes
Just have four units instead of five
o Ionotropic glutamate receptors
AMPA, kainite, and NMDA subtypes
Agonist Spectrum
o Similar concept applied to G-protein linked receptors
o Full Agonist
Conformational change to the receptor to open the ion channel to the
maximal ability
Triggers maximum amount of downstream activity
Can be opened even more than full agonist
o Requires help of a second receptor site
A positive allosteric modulator (PAM)
o Antagonist
Stabilize the receptor in the resting state
The resting state is not a fully closed ion channel
o There is some flow of ions even in the absence of an agonist
o Occasional opening of the channel in the absence of an agonist
or when an antagonist is present
Called constitutive activity
Bring it back to baseline state
Does NOT block constitutive activity
o Partial Agonist
Ion channel opens more frequently than the resting state but less than that of
a full agonist
Depends on how close to a full agonist or silent antagonist
Can modulate both excess and deficiencies
o Stabilizers
When full agonist is not present partial agonist will be a net agonist
When a full agonist neurotransmitter is present partial agonist will
be a net antagonist
o It will decrease the level of full signal output to a lesser level but
not to zero
o Inverse Agonists
Produce a conformational change at the receptors that first closes the
channel and then stabilizes it into an inactive form
Inactive form is a functional reduction in the following signal
transduction
o Even less than that of the resting state
o Opposite of a full agonist
States of Ligand Gated Channels
o Resting state
o Channel open state
o Channel closed state
o Desensitization
How targeting ion channels causes alterations in synaptic neurotransmission that are
linked to the therapeutic actions of various drugs
o Ligand-gated ion channels
o Voltage-sensitive ion channels
Ligand-gated Ion Channels as Targets of Psychopharmacological
Drug Action
Ligand-gated ion channels, ionotropic receptors and ion-channel-linked receptors
o Neurotransmitter binds to a gate-keeper receptor on an ion channel
This causes conformational change in the receptor that opens the ion channel
Neurotransmitter/drug/hormone ligand
Since ion channels are also receptors they are ionotropic receptors
o Fifth of psychotropic drugs act at these receptors
Treatment of anxiety and insomnia including benzodiazepines
Drugs that act on these receptors have an almost immediate effect
o Contrasted with G protein linked receptors which have a delay
d/t awaiting initiation of changes in cellular functions activated
through the signal transduction cascade.
Ligand Gated Ion Channels – Structure and Function
Comprised of several long strings of amino acids assembled as subunits around an ion
channel
o Multiple binding sites are on the subunits for everything from neurotransmitters to
drugs
Several sites where some ions travel through a channel and others also bind
to the channel
Allosteric modulators:
o Natural substances or drugs that bind to a site different than
where the neurotransmitter binds
o Can increase or decrease the sensitivity of channel opening
Pentameric Subtypes
o Assembled from five protein subunits pentameric
Each have four transmembrane regions
Some receptor sites are in the channel but also many different
locations outside of the channel
o This structure is typical for GABA receptors, nicotinic cholinergic
receptors, serotonin 5HT3 receptors and certain glycine
receptors
Acetylcholine nicotinic receptors
GABA GABA receptors (3 different subunits)
Glycine Strychnine-sensitive glycine receptors
Serotonin 5HT3 receptors
Tetrameric Subtypes
o Ligand-gated ion channels for glutamate
Comprised of subunits that have three full transmembrane regions and a
fourth re-entrant loop
Rather than four transmembrane regions
When four copies of these subunits are selected, they come together
, o Form a fully functional ion channel in the middle with the four re-
entrant loops lining the ion channel
Analogous to pentameric subtypes
Just have four units instead of five
o Ionotropic glutamate receptors
AMPA, kainite, and NMDA subtypes
Agonist Spectrum
o Similar concept applied to G-protein linked receptors
o Full Agonist
Conformational change to the receptor to open the ion channel to the
maximal ability
Triggers maximum amount of downstream activity
Can be opened even more than full agonist
o Requires help of a second receptor site
A positive allosteric modulator (PAM)
o Antagonist
Stabilize the receptor in the resting state
The resting state is not a fully closed ion channel
o There is some flow of ions even in the absence of an agonist
o Occasional opening of the channel in the absence of an agonist
or when an antagonist is present
Called constitutive activity
Bring it back to baseline state
Does NOT block constitutive activity
o Partial Agonist
Ion channel opens more frequently than the resting state but less than that of
a full agonist
Depends on how close to a full agonist or silent antagonist
Can modulate both excess and deficiencies
o Stabilizers
When full agonist is not present partial agonist will be a net agonist
When a full agonist neurotransmitter is present partial agonist will
be a net antagonist
o It will decrease the level of full signal output to a lesser level but
not to zero
o Inverse Agonists
Produce a conformational change at the receptors that first closes the
channel and then stabilizes it into an inactive form
Inactive form is a functional reduction in the following signal
transduction
o Even less than that of the resting state
o Opposite of a full agonist
States of Ligand Gated Channels
o Resting state
o Channel open state
o Channel closed state
o Desensitization
