1 Bi 1 “Drugs and the Brain” Lecture 22 Revised 5/18/06 Monday, May 15, 2006 1. Long-QT...
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Transcript of 1 Bi 1 “Drugs and the Brain” Lecture 22 Revised 5/18/06 Monday, May 15, 2006 1. Long-QT...
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1
Bi 1
“Drugs and the Brain”
Lecture 22 Revised 5/18/06
Monday, May 15, 2006
1. Long-QT syndrome;
2. Epilepsy
3. Huntington’s Disease
The final in-class slide (but not the posted slides) has a 1-point extra credit question.
You may not communicate this question to another student; no collaboration.
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Action potentials and the electrocardiogram
Electrocardiogrammeasured on the skin
Action Potentialmeasured with
intracellularelectrode
P
S
R
T
Q
K+ channels conductNa+ channels conduct
~ 100 V
~ 100 mV
~ 1 sec
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3
Monday, May 15. 2006 8:52 AM Kaiser Sunset Facility
Cardiology Lab, Treadmill facility
Part of Bi1 lecturer
Bi1 lecturer’sbaseline EKG
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An approximate explanation for the electrocardiogram, slide 1
The left ventricle pumps against the greatest resistancetherefore it has thickest walls; therefore its currents are the largest; therefore it contributes most of the ECG.
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An approximate explanation for the electrocardiogram, slide 2like Lecture 6
CE
G
Na+ K+ Cl-extracellular
cytosol
CE
G
Na+ K+ Cl-
ClKNai
gEVdt
dVCI
iii
,,
;)(
extRextext IRV
The capacitive currents are largest
An extracellular
electrode pair
records IR drops
proportional to the
(absolute value) of
the 1st derivative of
membrane potential.
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6
chest
leg
extRextext IRV
Only a small fraction of the current flows across the resistance between chest and a limb.
This produces a V ~ 103 times smaller than the transmembrane potential.
The ECG records this signal
An approximate explanation for the electrocardiogram, slide 3
CE
G
Na+K+
Cl-
extracellular
intracellular
CE
G
Na+K+
Cl-
extRextext IRV
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7
Action potentials and the electrocardiogram
Electrocardiogrammeasured on the skin
Action Potentialmeasured with
intracellularelectrode
P
S
R
T
Q
K+ channels conductNa+ channels conduct
~ 100 V
~ 100 mV
~ 1 sec
![Page 8: 1 Bi 1 “Drugs and the Brain” Lecture 22 Revised 5/18/06 Monday, May 15, 2006 1. Long-QT syndrome; 2. Epilepsy 3. Huntington’s Disease The final in-class.](https://reader035.fdocuments.in/reader035/viewer/2022062716/56649ddc5503460f94ad33e5/html5/thumbnails/8.jpg)
8
ElectrocardiogramAction Potential
Two classes of V-dependent channel explain cardiac electrophysiology in long-QT Syndrome. ~ 8 genes (complementation groups)
Q-T
P
S
R
T
Q
a heart-specific Na channel fails to inactivate completely
Or, one of several heart-specific K channels fails to activate
Normal heart rhythm
Arrhythmia
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Primary subunit Auxiliary subunit
KvLQT2
hERG
Human ether-a-go-go related gene
KCNE2
(MiRP1)
A cardiac K channel is also the target for drug-induced arrhythmias
P
Seldane® blocks hERG and was pulled from the market;
Allegra® does not
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10
Epilepsies: Repeated Seizures
Seizure: Massive derangement of brain function caused by excessive and synchronized function in a group of neurons.
A seizure can range from a “focal” 3-sec loss of consciousness, barely noticeable (like a “space out”) . . .
to a “generalized” event that causes a person to tense for several sec before a several sec jerking of his entire body.
Prevalence: ~ 5% of the general population experiences one or more seizures. The repeated seizures termed epilepsy occur in ~0.5% of the population.
Causes: brain injury (included a traumatic blow to the head), chronic illness, and inherited vulnerabilities .
Genetics: ~ 50% of epilepsies involve an inherited vulnerability.
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Epilepsies caused by Bi 1 Molecules
Genetics: ~ 50% of human epilepsies involve an inherited vulnerability.
Many knockout mice have seizures. Most of these genes are not associated
with human epilepsies.
Nestler Table 21-3 lists ion channel defects that produce some inherited
epilepsies (also discussed in Problem set 7).
KNCQ, a family of K channels (loss of function).
SCN, a Na channel (gain of function).
CHRN, nicotinic acetylcholine receptors (gain or loss, still uncertain).
Problem Set 6, Q1; see next slides.
In general, the causal links are less well understood than for long-QT
syndrome.
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First described as a disease, 1994.
The first epilepsy gene mapped and sequenced (1995).
Seizures arise during phase 2 sleep (rather than “rapid eye-movement sleep”;
Sometimes confused with nightmares.
Some patients display abnormal brain waves (as in Nestler Figures 21-5, 21-6).
Controlled by carbamazepine, not by valproate
An exemplar inherited epilepsy:Autosomal dominant nocturnal frontal lobe epilepsy.
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Binding region
Membrane region
Cytosolicregion
Colored by secondary
structure
Colored by subunit(chain)
Nearly Complete Nicotinic Acetylcholine Receptor (February, 2005)
http://pdbbeta.rcsb.org/pdb/downloadFile.do?fileFormat=PDB&compression=NO&structureId=2BG9
~ 2200 amino acids in 5 chains
(“subunits”),
MW ~ 2.5 x 106
from Lecture 3:
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How the binding of agonist (acetylcholine or nicotine) might open the channel: June 2003 view
M2
M1
M3
M4
Ligand-bindingdomain
from Lecture 3:
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ADNFLE and slow-channel myasthenic syndrome
Aligned Sequences of Mouse Muscle AChR M2 Domains
M2M1 M3 M4
2' 6' 10' 14' 18'9'
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy
I T C I V L L S L T V F L L L I TL S LL
V
MMCT
TGTS
SSSA
IIII
SFNS
VAVV
LL
L
L
LL
STAA
LLQQ
TT
S
V
VV
FF FF
LLLL
LLFL
VL
L
ILII
VAAS
LLVV
Slow-Channel Myasthenic Syndrome:Abnormally long channel duration
LL
TV
L
X X X
T C I V L L A L T V F L L L I SL S K I V
22'
Ligand-binding domain IC loop
Muscle
Brain
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inside
Procaine Blocks Na+ Channels from inside the cell
procaineprocaine-H+
procaine-H+
Functioningchannel
“Trapped” or“Use-Dependent”
Blocker
from Lecture 8:
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Local anestheticsDental surgery (procaine = Novocain®)Sunburn medications
Antiarrhythmics (heart) “use-dependent blocker”example: (procainamide)
Antiepileptics / anticonvulsants (brain) “use-dependent blocker” (phenytoin = Dilantin® )
Na+ channel blockers in medicine
from Lecture 8:
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18Nicotinic acetylcholine receptor
Carbamazepine, an antiepileptic drug,
binds in the pore
Some drugs compete with nicotine or acetylcholine
~ 40 Angstroms(4 nm)
transmembranedomain
based on Lecture 3:
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19
Cystic Fibrosis
1. Clinical description
2. Genetics
3. Gene structure
4. CFTR as a protein
5. Physiology of CFTR
6. What’s wrong with F508?
7. The cholera connection
8. Selective advantage of CF?
9. Therapeutic approaches:Incremental approachesGene therapy
Huntington’s Disease
1. Clinical description
2. Genetics
3. Gene structure
4. Huntingtin as a protein
5. Physiology of huntingtin
6. What’s wrong with the HD protein?
from Lecture 21
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Onset at 30-40 yr. Neurons in the striatum and cerebral cortex die,
leading to movement disorders (“chorea”), dementia, and eventually death.
Woody Guthrie 1912-1967
Mother died of Huntington’s chorea; Woody began suffering in ~ 1945He had 8 children.
1. Clinical description
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Again, we highlight neurons that make dopamine; here, note their postsynaptic targets in the striatum
Nestler Figure 8-6
from several previous lectures
“striped” GABA-producing“medium spiny” neurons
die in HD
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Huntington’s is a rare autosomal dominant disease (1 in 104 - 105 persons).
heterozygousmutant parent
“carrier”
HD
WT huntingtin
HD phenotype
homozygousWT parent
normal phenotype
like Lecture 21
WT huntingtin
WT huntingtin
HD
WT
HD phenotype
heterozygous“carrier”
HD
WT
HD phenotype
heterozygous“carrier”
WT
normal phenotype
homozygousWT
WT
normal phenotype
homozygousWT
WT WT
Dominance:50% of offspring have HD
2. Genetics
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First localized to 4p16.3 (~ 2.2 Mb) in 1983.
Gene product identified in 1993.
(from Lecture 20)
210 kb in length
67 exons, 3144 amino acids = 9432 nt coding region (~ 4% of the gene)
Personal decision: does a person at risk for HD submit to the decisive test based on DNA sequencing?
Mutation
5’ (N-terminus) 3’ (C-terminus)
3. Gene structure
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A CAG repeat, encoding glutamine,
is amplified. When (CAG)n grows
beyond n = 42, the disease occurs.
As n increases, age of onset
decreases.
Eight other human
neurodegenerative diseases are
caused by expanded triplet
repeats.
A baffling aspect of these diseases:
the proteins are expressed widely
in brain and other tissues,
yet each is toxic in a different,
highly specific group of neurons
and produces a distinct pathology.
4. Huntingtin as a protein
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Mice expressing mutant huntingtin exhibit a progressive neurologic phenotype with many of the features of HD, including -choreiform movements, -involuntary stereotypic movements, -tremor, and epileptic seizures, -nonmovement disorder components.
Evidently the mutant huntingtin has a destructive effect that is not provoked by wild type huntingtin;
thus HD is produced by a “gain-of-function” mutation.
5. Physiology of huntingtin
We don’t know the normal function of huntingtin.
“Knockout mice” for huntingtin die early in embryonic development, before the nervous system develops.
6. What’s wrong with the mutant huntingtin?
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An N-terminal fragment of huntingtin containing the polyglutamine stretch
accumulates as aggregates in cells.
The aggregates often appear in the nucleus.
When this fragment is expressed in mice,
or even in yeast,
the fragment aggregates as well.
It is not known whether the fragment is itself toxic, or whether the nuclear
localization is important for toxicity.
Huntingtin interacts with several other proteins in the cell.
Improper protein aggregates in HD
Nucleus
aggregate
aggregate
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Seymour Benzer found recently that
polyglutamine repeats also distort the
development of fruit fly eyes.
The polyglutamine repeat has been
tagged with GFP, and the proteins
clearly aggregate
Normal development can be “rescued”
with “chaperone” proteins, which help to
fold or eliminate misfolded proteins.
But the aggregates remain, suggesting
that the aggregates themselves are not
toxic.
Drosophila provides insights, as usual
wild typefly
fly expressing
polyglutamine repeats
glutamine repeats plus “chaperone” proteins
GFP
low-powerelectron microscope
lightmicroscope
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CFTR-F508
N
CR-domain
Cl- out
in
from lecture 21
Misfolded mutant proteins: a postulated common theme in inherited disease
polyglutamine forms-sheets
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< 10 nm
(FRET) detects polyglutamine aggregates
Cyan Fluorescent Protein (CFP) Yellow Fluorescent Protein (YFP)
blue photon
virtualcyan photon
yellow photon
like Lecture 11
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No interaction, no FRET
fused toYFP
fused toCFP
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Aggregation leads to FRET
fused toYFP
fused toCFP
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A type of fluorescence microscopy: fluorescence recovery after photobleaching (Ataxin is another triple repeat protein)
2. Watch unbleached mobile GFP-tagged “short” ataxin (above) diffuse into the
square from other regions of the cell
But “long” ataxin in aggregates (below) is immobile for many minutes
PNAS (2002),99, 9310
1. Use a laser to bleach all the GFP-tagged protein within the rectangle
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33modified from Little Alberts 1st edition Fig 7-32
Controlled proteolysis takes place in the proteasome
from Lecture 18
Mutant huntingtin may escape proteolysis in proteasomes because
(1) there are no proteasomes in the nucleus
(2) mutant huntingtin may be in a complex that cannot be degraded
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Intracellular inclusions in some neurodegenerative diseases
Alzheimer’s Disease
Parkinson’s Disease
Huntington’s Disease
We don’t know whether these aggregates are part of the disease process,
Or simply relatively harmless epiphenomema.
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Bi 1
“Drugs and the Brain”
End of Lecture 22