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Chapter 3 summary of Stahl Psychopharmacology

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Summary of chapter 3 psychopharmacology with important figures and tables

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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

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