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Bi 1 “Drugs and the Brain”

Lecture 1

Monday, March 27, 2006

Organization of the Course

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http://www.its.caltech.edu/~bi1/

The Bi 1 2006Home Page

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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