Module 3 Weekly Note.

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Twelve-transmembrane

region transporter

~ 30% of psychotropic drugs

Seven-transmembrane region

G-protein linked

~ 30% of psychotropic drugs

Enzyme

~ 10% of psychotropic drugs

The Five Molecular Targets of Psychotropic Drugs

Four-transmembrane region

ligand-gated ion channel

~ 20% of psychotropic drugs

Six-transmembrane region

voltage-gated ion channel

~ 10% of psychotropic drugs

2-1

Key ligand-Gated Ion Channels Directly Targeted by Psychotropic Drugs

Neurotransmitter	Receptor subtype directly targeted	Pharmacological action	Therapeutic action
Acetylcholine	α4β2-nicotinic receptors	Partial agonist	Smoking cessation
GABA	GABA-A benzodiazepine receptors	Full agonist, phasic inhibition	Anxiolytic
	GABA-A non-benzodiazepine PAM sites	Full agonist, phasic inhibition	Improves insomnia
	GABA-A neurosteroid sites (benzodiazepine insensitive)	Full agonist, tonic inhibition	Post-partum depression Rapid-acting antidepressant Anesthetic
Glutamate	NMDA NAM channels sites/Mg2+ sites	Antagonist	Procognitive in Alzheimer disease
	NMDA open channel sites	Antagonist	Dissociative hallucinogen Anesthetic Pseudobulbar affect Agitation in Alzheimer disease Rapid-acting antidepressant Treatment-resistant depression
Serotonin	5HT3	Antagonist	Procognitive Antidepressant Reduce chemotherapy-induced emesis

Ligand-Gated Ion Channels Have a Gatekeeper

3-1

Pentameric Ligand-Gated Ion Channels

Neurotransmitter	Receptor Subtype
Acetylcholine	Nicotinic receptors (e.g., α7-nicotinic receptors; α4β2-nicotinic receptors)
GABA	GABA-A receptors (e.g., α1 subunits; γ subunits; δ subunits)
Glycine	Strychnine-sensitive glycine receptors
Serotonin	5HT3 receptors

4 Transmembrane Regions, 5 Subunits

3-2A

3-2B

3-2C

Tetrameric Ligand-Gated Ion Channels

Neurotransmitter	Receptor Subtype
Glutamate	AMPA (e.g., GluR1–4 subunits)
	KAINATE (e.g., GluR5–7, KA1–2 subunits)
	NMDA (e.g., NMDAR1, NMDAR2A–D, NMDAR3A subunits)

3 Transmembrane Regions, 1 Re-entrant Loop, 4 Subunits

3-3A

3-3B

3-3C

The Agonist Spectrum

3-4

agonist

channel in its resting state in the absence

of agonist

agonist binds to the receptor and the

channel is more frequently open

3-5AB

channel in its resting state

antagonist binds to the receptor, not affecting the frequency of opening of the channel compared to the resting

state of no agonist

antagonist

3-6AB

antagonist

the agonist causes the channel to become

open more frequently

agonist

the antagonist takes over and puts the channel back into the resting state

agonist

antagonist

3-7AB

channel in its resting state

partial

agonist

partial agonist binds to the receptor and

causes it to open more frequently than

the resting state but less frequently

than with a full agonist

3-8AB

channel in its resting state

the full agonist opens the channel

maximally and frequently

the partial agonist

causes the

channel to open

more frequently;

in this case the

partial agonist is

having a net

agonist action

the partial agonist

causes the

channel to open

less frequently;

in this case

the partial agonist is

having a net

antagonistic action

3-9

partial

agonist

antagonist

partial agonist binds to the receptor and

causes it to open more frequently than

the resting state but less frequently

than with a full agonist

the antagonist causes the channel

to return to baseline

antagonist

3-10AB

channel in its resting state

inverse agonist

channel closed

the inverse agonist causes the channel to open very infrequently and eventually stabilizes it in an inactive state

channel closed

and inactivated

3-11AB

antagonist

the inverse agonist causes the channel

to stabilize in an inactive form

inverse agonist

the antagonist returns the channel

to the resting state

antagonist

3-12AB

resting state stabilized

by antagonist

resting state

inactivated state possibly reversed

immediately by an antagonist

closed state caused

by inverse agonist

3-13

channel in

resting state

channel open

channel closed

channel desensitized

channel inactivated

3-14

desensitized state

activated by prolonged agonist

open state

activated by acute agonist

resting state

inactivated state

not immediately reversed by

removal of agonist

order of hours

3-15

binding site

within

membrane

neurotransmitter

PAM

When a neurotransmitter binds to receptors making up an ion channel, the channel

opens more frequently. However, when BOTH the neurotransmitter and a positive allosteric modulator (PAM) are bound to the receptor, the channel opens much more frequently, allowing more ions into the cell.

3-16

neurotransmitter

NAM

When a neurotransmitter binds to receptors making up an ion channel, the channel

opens more frequently. However, when BOTH the neurotransmitter and a negative allosteric modulator (NAM) are bound to the receptor, the channel opens much less frequently, allowing fewer ions into the cell.

3-17

Ionic Components of an Action Potential

Na+

Ca++

K+

3-18

voltage-sensitive sodium channel (VSSC)

voltage-sensitive calcium channel (VSCC)

outside the cell

inside the cell

Na+

Ca++

3-19

Four Subunits Combine to Form the Alpha Pore Subunit, or Channel,

for Sodium of a VSSC (Voltage-Sensitive Sodium Channel)

outside the cell

inside the cell

pore inactivation

outside the cell

inside the cell

outside the cell

inside the cell

pore inactivation

Na+

3-20

Three States of a Voltage-Sensitive Sodium Channel (VSSC)

closed and inactivated

inactivated

open

3-21

Four Subunits Combine to Form the Alpha Pore Subunit, or Channel,

for Calcium of a VSCC (Voltage-Sensitive Calcium Channel)

outside the cell

inside the cell

snare

outside the cell

inside the cell

Ca++

outside the cell

inside the cell

3-22

Opening a Presynaptic Voltage-Sensitive N or P/Q

Calcium Channel: Triggers Neurotransmitter Release

glutamate

vesicle

snare

Ca++

3-23

Docking of Synaptic Vesicle with Presynaptic Membrane,

VSCC (Voltage-Sensitive Calcium Channel,) and Snare Proteins

3-24

Summary: From Presynaptic to Postsynaptic Signal Propagation

reception

integration

chemical encoding

electrical encoding

signal propagation

presynaptic signal transduction

postsynaptic signal transduction

reception

integration

chemical encoding

signal propagation

presynaptic signal transduction

3-25

VSSC

VSCC

neurotransmitter

vesicle

Na++

action potential

3-26

VSSC

Ca++

VSCC

3-26

Subtypes of Voltage-Sensitive Calcium Channels (VSCCs)

Type	Pore-forming subunit	Location	Function
L	Cav 1.2, 1.3	Cell bodies, dendrites	Gene expression, synaptic integration
N	Cav 2.2	Nerve terminals Dendrites, cell bodies	Transmitter release Synaptic integration
P/Q	Cav 2.1	Nerve terminals Dendrites, cell bodies	Transmitter release Synaptic integration
R	Cav 2.3	Nerve terminals Cell bodies, dendrites	Transmitter release Repetitive firing, synaptic integration
T	Cav 3.1, 3.2, 3.3	Cell bodies, dendrites	Pacemaking, repetitive firing, synaptic integration

Module 3 Weekly Note.

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