Drugs&brain mini lectures_1-10

“Drugs and the Brain”Drugs and the Brain
miniLecture 1A
O i ti d O i d l t A
© 2012 California Institute of Technology
Organization and Overview module, part A

What’s a Drug?
nicotine procaine botulinum toxinmorphine
CH3
N
N

Introducing the Central Nervous System
Brain
F t Back
Top “dorsal”
Brain
Front
“rostral”
Back
“caudal”
Bottom “ventral”
Spinal cord

The synapse is a point of information processing
presynaptic neuron
postsynaptic neuronNestler, Hyman, Malenka, Molecular Neuropharmacology,
© McGraw-Hill Professional Publishing
An adult human brain contains ~ 1011 neurons,
and each of these might receive 103 synapses apiece
Box 2 - 2 Figure A
g
and each of these might receive 103 synapses apiece,
for a total of 1014 synapses.
Most of these synapses form during the first 2 yr of life.
Thus 1014synapses/108 s = 106 synapses/s form in a fetus and infant!

Most drug receptors are membrane proteins (Nicotinic Acetylcholine Receptor)
~ 2200
amino acids
Binding
amino acids
in 5 chains
(“subunits”),
Binding
region
MW
~ 2.5 x 106
MembraneMembrane
region
Cytosolic
region
Colored by
secondary
structure
Colored by
subunit
(chain) eg o
http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=32169

Drug receptors are proteins.
Here’s the acetylcholine binding protein interfacial “aromatic box” occupied by nicotine
Y198
C2C2
W149
B
Y93Y93
A
Y190
C1
non-W55
D
(Muscle Nicotinic numbering)

Part 1: Drugs Activate and Block Ion Channels
Ligand-binding
region
acetylcholine
or
nicotine
~ 100 ÅM1
acetylcholine
or
nicotine
acetylcholine
or
nicotine
(10 nm)
M2
M1
M3
M4

Part 1: Drugs Activate and Block Ion Channels
DDrug
Receptor
current
time

N t itt h Ho fast? How far?
Part 2: Drugs Act on G protein pathways
Neurotransmitter or hormone
binds to receptor
activates
G protein
How fast?
100 ms to 10 s
How far?
Probably less 1 m
Effector:
enzyme or channel
G protein
outside
   
inside
 
GTP GDP + Pi

Downstream from GPCRs are intracellular messengers.
We have several ways to measure them.
Live-cell imaging is one way. Biochemistry is another.Live cell imaging is one way. Biochemistry is another.
Fluorescence
Microscopy
Alberts et al., Essential Cell Biology,
© Garland Science

See two items on the course Web site:
Henry Lester’s sources of research funding; and the disclaimer about medical advice
End of Organization and overview module, part A

“Drugs and the Brain”
Organization and overview module, part B: Diseases

Antidepressants Att ti d fi it
Part 3: Drugs Act on Transporters
Antidepressants
(“SSRIs” =
serotonin-selective
reuptake inhibitors):
Attention-deficit
disorder medications:
p )
Prozac, Zoloft, Paxil,
Celexa, Luvox
Drugs of abuse:
Ritalin, Dexedrine,
Adderall
Drugs of abuse:
Trademarks:
Drugs of abuse:
MDMA
Drugs of abuse:
cocaine
amphetamine
Presynaptic
terminals
Na+-coupled
cell membrane
serotonin
transporter
Na+-coupled
cell membrane
dopamine
transportertransporter transporter
+ H
cytosol
outside
13N
H
HO NH3
+
HO
HO
H2
C
C
H2
NH3
+
outside

amphetamine* phencyclidine
Targets for Recreational Drugs
p
cocaine
phencyclidine
nicotine
neurotransmitter
transporters
postsynaptic
cell
neurotransmitter-activated
channels
GPCRGPCR
G protein-activated
channels
N
C
enzymes

LSD
morphine-heroin
tetrahydrocannabinol ?alcohol?
caffeine*
(*= intracellular target)

1 Tolerance
Three general components of addiction
1. Tolerance
2. Dependence
3. Goal-seeking behavior
Tolerance
a. Metabolic tolerance:
Metabolism of the drug proceeds more efficiently.
This occurs primarily in the liver.
It f t f d i l di i i d i illiIt occurs for many types of drugs, including aspirin and penicillin.
b. Cellular tolerance:
Individual neurons or neuronal circuits become less responsive to the drug.

Components of nicotine dependence
RewardReward
Cognitive Sensitization
Stress Relief
Weight control Behavior
Circuits
Synapses
Weight control
Self-medication in schizophrenia
Changes in the Brain during Chronic Exposure to Nicotine
Neurons
Intracell.
Bindingg
Nic vs ACh
Proteins
RNARNA
Genes

Possible molecular mechanism for changes with chronic nicotine:
Signal transduction triggered by a ligand-gated channel
receptor
tsqi
G protein
effector
intracellular
enzymechannel
effector
NMDA receptors
kinase
cAMPCa2+
messenger
NMDA receptors
and
nAChRs
Brunzell, Russell, & Piccotto,
J. Neurochem, 2003
phosphorylated
protein
are highly permeable to Ca2+
as well as to Na+.
17

Part 4: Drugs for neural diseasesg
catalytic protein
enzyme:
decarboxylase
Greek, “to leaven”
HO
H2
C NH3
+
HO
H2
C
C
NH3
+
decarboxylase
HO
HO 3
CO2
-
HO
HO C
H2
3
levodopa, “L-dopa”
zwitterionic
permeates into brain
dopamine
does not enter brain

Neurons that Make Dopamine Die in Parkinson’s Disease
Figure 8-6
Nestler, Hyman, Malenka, Molecular Neuropharmacology,

Some psychiatric drugs, their targets,
logP values, and half lives
antipsychotic antidepressant
recreational /
antipsychotic antidepressant
ketamine
(“special K”)
chlorpromazine
(Thorazine)
nicotine
acetylcholine receptor
abused / addictive
( special K )
NMDA glutamate receptor
logP 2.2, 3-5 hr
(Thorazine)
dopamine D2 receptor, GPCR
logP 5.2, 16-30 hr
acetylcholine receptor
logP 1.2, 0.5 -2 hr
fluoxetine
(Prozac)
clozapine (Clozaril)
5-HT2A serotonin receptor, GPCR (Prozac)
serotonin transporter
logP 3.4, 24-72 hr
logP 3.2, 8-12 hr

Bipolar Disease
Vi t V G h 1853 1890Vincent Van Gogh 1853-1890
750 paintings; 1600 drawings; 700 letters
Life history: born and raised in the Netherlands. Paris 1886-88
1887 1887-88
y
Arles 1888 (1st episode; cut off his own ear); hospitalized 1888-1890
Auvers-sur-Oise 3 months. Shot himself 7/27/1890
1886

David Helfgott plays
Rachmaninov Piano Concerto #3
C h Philh i O h tCopenhagen Philharmonic Orchestra,
1995
RCA Victor-BMG Classics
as in the movie “Shine”as t e o e S e
Born in Melbourne 1947
1962-1970 several schizophrenic
episodes
1966-70 Royal College of Music1966-70 Royal College of Music
1970-1980 Hospitalized in Australia
1984- present concert pianist
According to the biography by his wife,
his present medication consists of:
D2 receptor blocker for schizophrenia;D2 receptor blocker for schizophrenia;
anticholinergic for tardive dyskenesia

Contemporary ideas about psychiatric drugs
have emphasized binding to
the classical targets at synapses. . .
“Inside out” mechanisms emphasize binding to“Inside-out” mechanisms emphasize binding to
the same classical targets, but within the
endoplasmic reticulum and cis-Golgi

Eroom’s law applies especially to neural drugs
Scannell Nature Revs Drug Disc 2012Scannell, Nature Revs Drug Disc. 2012

Please see two items on the course’s Web page:
Henry Lester’s sources of research funding; and the disclaimer about medical advice
End of Organization and overview Modules

HO
N
O
HO
N
HO
CH3
morphinemorphine
Drugs and the Brain
miniLecture 2
What is a drug?
Types of drug molecules

drug
noun Origin: Middle English drogge Date: 14th century
1 a . . .
b : a substance used as a medication or in the preparation of medication
c : according to the Food Drug and Cosmetic Actc : according to the Food, Drug, and Cosmetic Act
(1) : a substance recognized in an official pharmacopoeia or formulary
(2) : a substance intended for use in the diagnosis, cure, mitigation, treatment,
ti f dior prevention of disease
(3) : a substance other than food intended to affect the structure or function of
the body
2 . . .
3 : something and often an illegal substance that causes addiction habituation or a3 : something and often an illegal substance that causes addiction, habituation, or a
marked change in consciousness
© Merriam-Webster, Inc
http://www.merriam-webster.com/dictionary/drug

Trivial names and Structural Formulas
botulinum toxinnicotine procaine morphine
H2C
N
H3CH2C CH2CH3
HO
N
CH3
N
O
CH2
C O
N
O
N
N
HO
CH3
morphine
NH2

This session’s drugs exemplify the concepts in “Drugs and the Brain”
Drugs Activate (nicotine) and block (procaine) ion channels
Drugs act on G protein pathways (morphine)
Part 3: Drugs activate genes (nicotine, morphine)
Protein drugs may become more useful for neuroscience diseases
(botulinum toxin)
Not treated in this session:
Drugs act on neurotransmitter transportersDrugs act on neurotransmitter transporters

Atomic-scale Structures
nicotine procaine botulinum toxinmorphine
N
CH3
N
http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4914&loc=ec_rcs

Each moiety in a drug molecule has importance.
Example: procaine
Charged amine:
may bind to
H2C
HN
H3CH2C CH2CH3
+
may bind to
charged groups or π electrons
on the protein
Ester: hydrolyzed to
O
CH2
2 Ester: hydrolyzed to
terminate drug action
C O
Aromatic: may bind to
NH2
nonpolar groups on
the receptor protein
2

Formulas and molecular weights (MW)
nicotine procaine botulinum
toxin
morphine
C13H20N2O2
236
C10H14N2
162 ~150,000
C17H19NO3
285.3

Trademark Names
nicotine procaine
botulinum
toxin
morphine
D i ® Botox®
Marlboro®
Camel® Astramorph®,
Duracaine®
Novocain®
Botox®
Nicorette®
Nicoderm®
Kapanol®,
Skenan®
Nicoderm®

Type of CompoundType of Compound
hinicotine morphine
alkaloid
(Alkaloids are a group of nitrogenous organic compounds
that have physiological effects on humans).

procaine
procaine
local anesthetic
(S th ti i d)(Synthetic organic compound)

botulinum
botulinum
toxin
protein:protein:
Chain of amino-acid residues joined by peptide bonds

HO
N
O
CH3
HO
CH3
morphinemorphine
Drugs and the Brain
What is a drug?
End of module 2
Types of drug molecules

botulinum toxin
Drugs and the Brain
miniLecture 3
What is a drug?
Permeation into the brain, and botulinum toxin

Routes into the Nervous System
nicotine procaine botulinum
toxin
morphine
S k d I j t dS k dSmoked;
chewed;
Injected
Injected;
eaten
Smoked;
Injected;
skin patch suppository

RNH RNH +
H+
often the active
and predominant form
blood
RNH2 RNH3
+
Lipid barrier,
e. g. membrane(s)
mouth stomach or lungs
g ( )
mouth, stomach or lungs
RNH2 RNH3
+
H+
higher pH

Nicotine’s path from the lungs to the blood and the brain
CN NK 8 0
N
CH3
N
blood
H+
N
+
H3C
N
HpKa = 8.0
blood,
then brain
3 cells and 6 membranes
lungs
3 cells and 6 membranes
vaporized
N
CH3
N
N
+
H3C
N
H
H+
pKa = 8.0
vaporized
Most cigarettes also contain ammonium hydroxideMost cigarettes also contain ammonium hydroxide,
To maintain neutral pH
Tobacco leaves are roughly 5% nicotine by weight.

100
Blood nicotine concentrations during and after a cigarette
60
80
20
40
60
nM
0
20
0 50 100 150
smoking
min

Another example of neutral drug permeation.
In Parkinson’s Disease: most neurons that make dopamine die
catalytic protein
In Parkinson s Disease: most neurons that make dopamine die
The challenge: replace the dopamine in the brain
enzyme:
decarboxylase
Greek, “to leaven”
HO
H2
C NH3
+
HO
H2
C
C
NH3
+
decarboxylase
HO
HO 3
CO2
-
HO
HO C
H2
3
levodopa, “L-dopa”
zwitterionic
permeates into brain
dopamine
does not enter brain

Brain Other organs
Endothelial cells form the blood-brain barrier
“Tight junction” g
~ 10 m
Protein
Nonpolar molecule
Polar molecule (e. g., glucose)o a o ecu e (e g , g ucose)

Endothelial cells form the blood-brain barrier
Blood vessel
Blood
“Tight junction”
Glial foot
Endothelial cells lining the capillary
Red blood cells

The Structural BasisThe Structural Basis
of
Tight Junctions
extracellular
space
Alberts et al., Essential Cell Biology, © Garland Science

Drugs in the Body and in Cells
Acid-base equilibrium and permeability
Uptake from the stomach
Uptake from smoke
Crossing the cell membrane
Sh t i iti ti i lShort-circuiting synaptic vesicles
Neurotransmitter transport inhibitors
More in later
sessionsNeurotransmitter transport inhibitors
Blood-brain barrier:
sessions
molecular basis
an opportunity for drug specificity
a problem for drug deliverya problem for drug delivery

botulinum toxin
Drugs and the Brain
miniLecture 4
What is a drug?
Permeation into the brain, and botulinum toxin

More about Botulinum Toxin, which has Become a Modern Protein Drug
Botulinum toxin is made by Clostridium botulinum, an anaerobic bacterium.
“Botulism” comes from a German physician who noticed cases of paralysis associated withBotulism comes from a German physician who noticed cases of paralysis associated with
eating an uncooked smoked sausage in 1793. 13 people in Wildbad shared the sausage that
had been sitting for hours; all became ill and six died. (To describe their illness, the word
botulism was derived from the Latin botulus, for sausage.)botulism was derived from the Latin botulus, for sausage.)
The conditions beneath the skin of the sausage had been anaerobic (i.e., there was very little
oxygen in the meat) and enough time had elapsed to allow the clostridial bacteria to multiplyyg ) g p p y
and produce the toxin within the sausage.
Botulinum toxin is fatal in extremely low quantities (~ 1 molecule per synapse), because ity q ( p y p )
paralyzes muscles. 10-8 grams kills a mouse. The paralysis occurs because presynaptic
terminals cannot release transmitter.

The bacterium synthesizes botulinum toxin as a single protein chain,The bacterium synthesizes botulinum toxin as a single protein chain,
then cleaves the chain
The light chain enters cellsThe light chain enters cells,
then acts as an enzyme

Many diseases and discomforts are caused by excess muscle activity.
Botulinum toxin, injected in minute quantities,
blocks this excess activity and gives relief from squint and spasm.
Botulinum toxin also decreases frown lines (Botox®).

What are some possible new therapeutic uses for botulinum toxin?What are some possible new therapeutic uses for botulinum toxin?
Let’s examine the biomedical literature today:
http://www.ncbi.nlm.nih.gov/pubmed?term=botulinum%20toxin

Drugs and the Braing
End of module:
What is a drug?
botulinum toxin
What is a drug?
Permeation into the brain,
and botulinum toxin

Drugs and the Brain
Introduction to Drug Receptors
Most Drug Receptors are Proteins: Parts of a ProteinMost Drug Receptors are Proteins: Parts of a Protein

Receptor
a molecule on the cell surface or in the cell interior that has an affinity fora molecule on the cell surface or in the cell interior that has an affinity for
a specific molecule (the ligand).
Latin,
“to tie”to tie
Most drug receptors are proteins.
Greek “first”Greek, first

shortest: 9
longest: 5500
“ tid ”
side chains
“peptide”
or
amide bonds
20 types
side chains
link the
“backbone”backbone
or
“main chain”
or
“-carbons”
Alberts et al., Essential Cell Biology, © Garland Science

Proteins contain a few structural motifs:
 helices  sheets
alpha-helix-alphabetical.pdb beta-sheet-antiparallel.pdb
Hide side chains
Show H-bonds and distances
Show ribbons & arrows
Show side chainsShow side chains
Show Van der Waals radii
Show stereo view

Drugs and the Brain
End of Module,
“Introduction to Drug Receptors:
Parts of a Protein”Parts of a Protein”

Drugs and the Brain
Introduction to Drug Receptors
Most Drug Receptors are Proteins: More about Receptor ProteinsMost Drug Receptors are Proteins: More about Receptor Proteins

Nearly Complete Nicotinic Acetylcholine Receptor (February, 2005)
~ 2200
amino acids
Binding
amino acids
in 5 chains
(“subunits”),
Binding
region
MW
~ 2.5 x 106
MembraneMembrane
region
Cytosolic
region
Colored by
secondary
structure
Colored by
subunit
(chain) eg o

The AChBP interfacial “aromatic box” occupied by nicotine (Sixma, 2004)
Y198
C2
W149
BB
Y93
A
non-W55
D
Y190
C1
(Muscle Nicotinic numbering)
61

Simple views of nicotinic acetylcholine receptor
5 subunits
each subunit has 4 -helices
in the membrane
(20 membrane helices total)
(extracellular)

How does binding of a drug activate a receptor protein?
We’ll discuss this in a future session,
but here we note that most receptors are allosteric proteins
Ligand-binding
region
p p
Greek, “other” + “body”
acetylcholine
or
nicotine
~ 100 ÅM1
acetylcholine
or
nicotine
acetylcholine
or
nicotine
(10 nm)
M2
M1
M3
M4 An allosteric protein binds a ligand at one
site affecting the function of a different sitesite, affecting the function of a different site
within the same protein.

Concepts associated with Allosteric Proteins
Conformational changes. Several subunits.
In some allosteric proteins, all subunits undergo “concerted” transitions
between two at least two statesbetween two at least two states
(in a ligand-gated channel, “open”, “closed”, “desensitized”)
Some allosteric proteins undergo “sequential” transitions,
as though the ligand “induces” a fit of the protein.
The subunits may transition independently.
“Shape-shifting” protein is a more general termShape shifting protein is a more general term.
These concepts are being refined and complicated as we obtain
atomic-scale structural information about receptor proteins
i h i i f i lin their various functional states.

W t t di t th t t f t i i l f k i itWe cannot yet predict the structure of a protein simply from knowing its
sequence.
This is especially true for membrane proteins like receptors.p y p p
But “structure prediction” techniques are improving.

D d th B iDrugs and the Brain
End of Module,
“Introduction to Drug Receptors:
More about Receptors as Proteins”

Drugs and the Brain
miniLecture 7
Introduction to Mammalian Brains:
Neuronal circuits, neurons, and synapses

The Central Nervous System
Brain
F t Back
Top “dorsal”
Brain
Front
“rostral”
Back
“caudal”
Bottom “ventral”
Spinal cord

Function is often localized to specific brain regionsFunction is often localized to specific brain regions
movement
sensationssensations
vision
BackFrontrostral caudal
reward
judgement
reward
acetylcholine
(nicotine)
and
memory
coordinationand
dopamine
coordination

A typical pathway:
sensation of painp
and the reaction
to pain

Spinal reflexes, such as the knee-jerk, involve just two neurons.
sensory neuron
motor neuron
the sensory neurons act like
strain gauges wrapped aroundstrain gauges wrapped around
special muscle fibers.

Parts of two neurons
Presynaptic Postsynaptic
Excitatory
terminal
Inhibitory
terminal presynaptic
terminal
neuron neuron
Greek “axis”
axon
terminalGreek, axis
dendrites
cell
body
presynaptic
synaptic
nucleus
presynaptic
terminal postsynaptic
dendrite
Greek, “tree”
y p
cleft
direction of information flow

The synapse is a point of information processing
Greek, “connection, junction”
presynaptic neuron postsynaptic neuron
Box 2-2 Figure A
An adult human brain contains ~ 1011 neurons,
and each of these might receive 103 synapses apieceand each of these might receive 103 synapses apiece,
for a total of 1014 synapses.
Most of these synapses form during the first 2 yr of life.
Thus 1014synapses/108 s = 106 synapses/s form in a fetus and infant!

Chemistry is a Language of the Brain, for Instance at Synapses
cytosol
cytosol
receptor
cytosol
synaptic cleft
receptor
presynaptic
terminal
postsynaptic
dendrite
transmitter molecules
receptor
direction of information flow

Drugs and the Brain
End of LectureEnd of Lecture,
“Introduction to Mammalian Brains “

Drugs and the Brain
Sample Recordings and Techniques for Studying the Brain:
The frequency of a neuron’s action potentials (nerve impulses) is the mostq y p ( p )
important parameter in brain signalling . . . and in drug effects.

Electricity is also a Language of the Brain.
Intracellular recording with sharp glass electrodes.
1. A current applied by the experimenter increases firing rates
V, I,
http://info.med.yale.edu/neurobio/mccormick/movies/rly_exp.avi
Prof. David McCormick’s data

Intracellular recording with sharp glass electrodes.
2. Artificially applied acetylcholine acts on muscarinic receptors to
change the membrane potential, increasing action potential
frequency.
V
Prof. David McCormick’s data
(The spikes in these examples are about 100 mV in amplitude)
http://info.med.yale.edu/neurobio/mccormick/movies/ach_fin.avi

Modern Neuroscience Techniques:
Time scales, Distance Scales, and Invasiveness
magnetoencephalography
+
event-related potentials
functional magnetic
resonance imaging
positron
emission tomography
Optical
Dyes
Silicon Array
Microlesions
2-deoxyglucose
Intracellular Patch/Sharp
Extracellular Single Unit or Tetrode

Drugs and the BrainDrugs and the Brain
End of lecture on
“Sample Recordings and Techniques for Studying the Brain”Sample Recordings and Techniques for Studying the Brain

H2O K+ ion
carbonyl
miniLecture 9
Origin of the Resting Potential;
Electrical Aspects of Ion Channels

Storing energy in a concentration gradient
without osmotic stress:
Simply reverse the ratio of Na+ and K+
E l
Na+ Na+Na+
Simply reverse the ratio of Na+ and K+
External
Monovalent cations:
High Na+
Low K+Low K+
Na+
Internal:
L N +
K+
K+ K+
Na+
Na+
K+
Low Na+
High K+
K+
NNa+
Na+ K+

Typical extracellular and cytosolic ion concentrations (mammalian cell)
Extracellular
conc
Intracellular
(Cytosol)( y )
major
monovalent
Ions
Na+ 145 mM 15 mM
K+ 4 mM 150 mM
Cl- 110 mM 10 mMIons Cl 110 mM 10 mM
divalent
ti
Ca2+ 2 mM 10-8 M
cations Mg2+ 2 mM 0.5 mM
P -2 2 mM 40 mM
Other ions
Pi
2 mM 40 mM
H+ 10-7 M 10-7 M
Protein 0.2 mM 4 mM

Converting a concentration gradient
to an electrical potential:
Create permeability to one ionic species (K+)
Na+ Na+Na+
Create permeability to one ionic species (K+)
Lost positive charge
K+
Na+
K+
K+
leads to net negative
interior potential
Na+
Na+
K+
K+
K+ channels
Na+
Na+

The Nernst potential:
the energy of discharging the concentration gradient for K+ ions
balancesbalances
the energy of moving the K+ ions through the potential difference
K+K+
K+
K+
K+
K+
K+

;ln zFV
K
RTG i
 at equilibrium 0G ; therefore 



 iKRT
V ln
Deriving the Nernst Potential (Chemistry Units)
;ln zFV
K
RTG
o
 at equilibrium 0G ; therefore 




oKzF
V ln
(For K+
, z = +1)
A f ld i f K+
i ( )An e-fold ratio of K+
concentration ( oi KK  )
therefore leads to a potential difference of .
F
RT

K)J/(mol318R K)J/(mol31.8R
coul/mol,50096F
K300T
Therefore
F
RT
= mV25.8mJ/coul8.25 
Thus an e-fold concentration ratio gives a -25 8 mV membrane potentialThus an e-fold concentration ratio gives a -25.8 mV membrane potential.
And a 10-fold concentration gives a -59 mV membrane potential.

Deriving the Nernst potential
(physics units)
R = Nk, where N is Avogadro’s number and k is Boltzmann’s constant;
And F = Ne, where e is the charge on the electron.
Therefore mV8.25
1061
3001038.1
19
23





 

C
J
e
kT
F
RT
106.1  CeF
(we are familiar with the statement that kT = 26 meV)

Neurons are not Equilibrium SystemsNeurons are not Equilibrium Systems
Several types of channels of channels are open at once.
To analyze resting potentials under these circumstances,
we’ll switch to electrical calculations.

Atomic-scale structure of (bacterial) Na+ channels
Views
from the
extracellularextracellular
solution
Payandeh et al
electrically, open channel = conductor
Payandeh et al,
Nature 2011;
Zhang et al,
Nature 2012;
Views
from the
membrane
plane

H2O K+ ion
carbonyl
“D d th B i ”“Drugs and the Brain”
End of miniLecture 9

Na+ K+
G
E
miniLecture 10
El t i l A t f I Ch l
Electrical Aspects of Ion Channels

The miniature single-channel conductors add in parallel
GNa = Na GK = KNa Na K K
GNa
outside
GK
Na
E
=
GNa
E
GK
K
ENa
(+60 mV)
cytosol = inside
EK
(- 60 mV)
cytosol = inside
Na
Kirchhoff’s Current Law
(Conservation of Charge)
mostly Na+
mostly K+ K

The membrane potential at steady state
(not at equilibrium)(not at equilibrium)
N K+
Oversimplified view of
excitatory postsynaptic
responses
resting
potential:
outside
G
Na+ K+ responses
(see miniLecture 13):
Na+ channels open too
p
K+ channels
open
outside
E
G
V
E G E G
G G
K K Na Na


G GK Na

cytosol = inside

Two Major Roles for Ion Channels in Drugs and the Brain
[neurotransmitter or agonist]
Drugs at synapses:
openclosed
Drugs at synapses:
Future lectures:
electric field or drug
openclosed
Drugs at axons and
cell bodies

Na+ K+
G
Na
E
End of miniLecture 10

Drugs&brain mini lectures_1-10

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