1 bi 1 “drugs and the brain” lecture 1 monday, march 27, 2006 organization of the course
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Bi 1 “Drugs and the Brain”
Lecture 1
Monday, March 27, 2006
Organization of the Course
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•In the mid-1990’s, the Caltech faculty instituted a requirement that all students must take biology as part of the “core curriculum”
•We have ~220 freshmen
•~ 35 Biology majors and other interested Freshmen take a two-course intro to molecular and cellular biology
•~ 185 Freshmen take Bi 1 in the Spring
•Math, physics, chemistry, and engineering majors
•All believe that biology should be derived from first principles
Biology 1 at Caltech
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Henry Lester’s Goal: provide the principles that will allow Caltech grads to appreciate the progress in clinical neuroscience over the next 5-20 years
College freshmen are not interested in disease
Challenge: provide a “stealth” introduction to clinical neuroscience, while addressing Caltech students’ interest in quantitative descriptions
No illegal drugs, please
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Biology 1
“Drugs and the Brain”
How do we progress from biophysics to clinically relevant neuroscience?
1. quantitative descriptions
2. single-molecule phenomena
3. lots of Caltech connections
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A 20-minute survey of Bi 1
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nicotine(Nestler Fig. 12-4)
N
CH3N
procaine(Nestler p. 50)
O
CH2
H2C
NH2
C O
NH3CH2C CH2CH3
botulinum toxin(Nestler p. 203, 323)
N
O
HO
HOCH3
morphine
morphine(Nestler Fig. 16-3)
What’s a Drug?
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~ 100 Å(10 nm)
Most drug receptors are membrane proteins. Proteins are beautiful.
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http://www.its.caltech.edu/~lester/Bi-1/AChBP-2004-BindingSite.pdb
We’ll learn to view and manipulate pictures of molecules
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What is a Brain?
Front Back
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Electricity is a language of the nervous system
Nestler Figure 3-1B
Nestler Figure 3-1B
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presynaptic neuron postsynaptic neuron
The synapse is a point of information processing
An adult human brain contains ~ 1011 neurons,
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!
Nestler Box 2-3 Figure A
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Channel 1
Channel 2
Channel 3
Channel 4
Principle of the Stereo Tetrode
Voltage minus
Amp. Channel 1
Am
p. C
han
nel
4
Am
p. C
han
nel
3
Amp. Channel 2
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A functional magnetic resonance imaging (fMRI) image. This is the rear view of a human brain activation associated with performance of a task that utilizes motor, visual and planning cognitive processes. The subject was moving a joystick to follow a target around a video display.
http://www.cmrr.umn.edu/research/functional.shtml
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The Central Dogma of Drugs and the Brain, Part 1:
Drugs Activate and Block Ion Channels
Drug
Receptor
current
time
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~ 100 Å(10 nm)
Some drugs bind on the axis
Some drugs compete with nicotine
Drug interactions at the nicotinic acetylcholine receptor
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time constant= 1/(k21+ k23)
time constant= 1/k21
+
closed open
State 1 State 2
normal functionk21
closed opendrug
blockedsimple block
k21
closed opendrug
blockedfoot-in-the-door
k21
k32
all molecules begin here at
t= 0
Not allowed
k23 = k+[Drug]
k23 = k+[Drug]
etc
n =1
0
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in vitro RNA synthesisRNA polymerase promoter
DNA
measure
Site-Directed Mutagenesis on Ion Channels
Express by injecting into immature frog eggs
Mutate the desired codon(s)
measure
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Channels are miniature conductors that add in parallel
ENa
(+60 mV)
GNa = Na
=GNa
Na
Na
GK = K
EK (- 60 mV)
GKK
K
outside
inside
mostly K+mostly Na+
21Little Alberts Panel 1-1
22GTP GDP + Pi
Effector: enzyme or channel
outside
Neurotransmitter or hormonebinds to receptor
activatesG protein
How fast?100 ms to 10 s
How far?Probably less 1 m
inside
The Central Dogma of Drugs and the Brain, Part 2:Drugs Act on G protein pathways
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postsynapticcell
neurotransmittertransporters
neurotransmitter-activatedchannels
GPCR
G protein-activatedchannels
N
C
LSD
morphine-heroin
tetrahydrocannabinol
amphetamine*
cocaine
phencyclidine
nicotine
?alcohol?caffeine*
(*= intracellular target)
enzymes
Targets for Recreational Drugs
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Neurons that make dopamine; “pleasure/reward system” highlighted
Nestler Figure 8-6
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How do we study the fundamental bases of drug
addiction?Thomas Hunt Morgan Ed Lewis
Seymour Benzer
Drosophila melanogaster
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cytosol
nucleus
How fast?10 s to days
How far?Up to 1 m
kinase
phosphorylatedprotein
cAMPCa2+
intracellularmessenger
receptor
tsqiG protein
enzymechannel effector
membraneoutside
inside
outside
inside
The Central Dogma of Drugs and the Brain,
Part 3:Drugs Activate Genes
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Mid-Term Exam
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Genomics and genetics in Bi 1“Drugs and the Brain”
15, 17. Genomics
18. Implementing the Genetic Code: from DNA to Protein
20. Genetics: Formal and Molecular
21,22. Exemplar Simple Genetic Diseases: Cystic Fibrosis, long-QT syndrome, epilepsies
23. Stem cells and stem cell therapy
24. Another exemplar simple genetic disease: Huntington’s disease.
24,25 Schizophrenia, bipolar disorder, and the complex genetics of psychiatric diseases
27. Evolution 1: Inferences from Molecular Biology
28. Evolution 2: The eye as an example
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Single-molecule measurements in genomics
E = force x distance;force is generated by viscosity
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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
Cystic Fibrosis: A Genetic Disease
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David Helfgott playsRachmaninov Piano Concerto #3Copenhagen Philharmonic Orchestra, 1995RCA Victor-BMG Classicsas in the movie “Shine”
Born in Melbourne 1947
1962-1970 several schizophrenic episodes
1966-70 Royal College of Music
1970-1980 Hospitalized in Australia1984- present concert pianist
According to the biography by his wife,his present medication consists of:D2 receptor blocker for schizophrenia;anticholinergic for tardive dyskenesia
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Huntington’s Disease: Simple genetics, unknown mechanismOnset 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.
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1887 1887-88
Bipolar Disease
Vincent Van Gogh 1853-1890750 paintings; 1600 drawings; 700 letters
Life history: born and raised in the Netherlands. Paris 1886-88Arles 1888 (1st episode; cut off his own ear); hospitalized 1888-1890Auvers-sur-Oise 3 months. Shot himself 7/27/1890
1886
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July 1890
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Cell cycle and stem-cell therapy
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Neurons that make dopamine die in Parkinson’s Disease
Nestler Figure 8-6
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Testing our understanding of evolution: the eye
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Flightless cormorant
Voyages to the Galapagos
“Study nature, not books” (Louis Agassiz)
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Final Exam
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Bi 1 Fonts:Largest font size
Medium font size
Smallest font size
(Slide projector sound)
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Problem set #1 will be posted Tuesday on the Bi 1 Web Site;it’s a pdf.
Due next Monday 4/3 11 AM in the Bi 1 Closet
You might wish to inspect PS #1 before this week’s section meetings.
Bi 1 Home Page:http://www.its.caltech.edu/~bi1/
Bi 1 Collaboration policies:http://www.its.caltech.edu/~bi1/Bi-1-policy-sheet.pdf
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If you drop the course,
or if you register late,
please email Patricia Mindorff mindorff@caltech.edu
(in addition to the Registrar’s cards).
Also, if you want to change sections,
please email Patricia Mindorff mindorff@caltech.edu
Patricia Mindorff works 9 AM - 5 PM M-F
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