drugsandbrain materials background materials from lecture 14 2013 bi cns150

7/27/2019 Drugsandbrain Materials Background Materials From Lecture 14 2013 Bi CNS150

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6. Time frame for evolution of the major features

1. lens and

optics 2. photoreception

event

5. A master switch

that controls

differentiation

.

to the brain

3. retina

Bi / CNS / NB 150 Lecture 14Wednesday, October 30, 2013

Vision 1: Phototransduction and the Retina

Evolution of the Eye

Henry LesterChapter 26, co-written by Markus Meister 1


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6. Time frame for evolution of the major features

1. lens and

optics 2. photoreception

event

5. A master switch

that controls

differentiation

.

to the brain

3. retina

Bi / CNS / NB 150 Lecture 14Wednesday, October 30, 2013

Vision 1: Phototransduction and the Retina

2

Evolution of the Eye

Henry LesterChapter 26, co-written by Markus Meister


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Nothing in biology makes sense except in the light of evolution

Theodosius Dobzhansky

All modern biological processes evolved from related processes.

Every modern gene evolved from other genes.

Every gene has an ortholog in related species,

most genes have paralogs in the same species.

Because all vertebrate eyes are quite similar,

.

That two organisms share many orthologs is powerful evidence for the view

that those organisms are descended from a common ancestora central

aspect of evolution.3


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orthologs resemble each other

across species (mouse vs human )

paralogs resemble each other,

Example: globin genes

orthologs & paralogsHemoglobin paralogs in the human genomeHemoglobin paralogs in the mouse genome

chromosome

human vs mouse vs distant or closely, within a species

G vs A

Myr BPMyr BP

4


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The lens has an index of refraction greater than water,

1. Lens and optics

because it contains a high concentration of protein.

Many proteins different serve this purpose have been used in various animals.

ome o ese pro e ns, erme crys a ns, are a so enzymes

that perform metabolic functions in other tissues.

Apparently the only requirement is that the protein have good solubility and no

attached groups (such as vitamins) that might absorb light.

from Lecture 1 How much is 4 mM protein?

.

An average residue has a molecular mass of 110.

Therefore the average protein has a molecular mass of 55,000.

( 4 x 10-3 mol/liter) x (5.5 x 104 g/mol) = 2.2 x 102 g/l = 220 g/l.

The cell is ~22% protein!5


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Pax-6 ortholo s occur in h la as diverse as as mammals insects and molluscs.

Pax-6, a transcription factor with orthologs in many species

Many genes, including crystallins, have acquired a Pax-6 responsive element

Pax-6 contains a homeo domain & another-DNA binding domain

-

Ey (Drosophila)Presence of multiple

sufficient gene regulatory

mechanisms can underlie

ene sharin Existing proteins have been

functions.

Which way were they

adopted?

Probably the use in the lens

.

Evidently several distinct

transcription factors can

6

share activation of a given

gene.


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The aperture mechanism: controlled by smooth muscles

blocker: atropine fromAtropa belladonna

single

smooth muscle cell

Contracts and thickens:

leads to smaller pupil

muscarinic synapse

inextensible fibers

Innervated smooth muscles control: In each case, the nervous system has

evolved circuits that

,

peristaltic activity of the intestinal tract,

diameter of the bladder neck

from sensors and

(2) employ smooth muscles in ahomeostatic loop. 7


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2. The photoreception event

Photoreceptor organs have evolved independently at least 40 times, each

t me respon ng to t e v s e spectrum an near- .

How do we explain the use of a limited part of the spectrum?

Infrared light is not sufficiently energetic to provoke photochemistry such

as cis-trans isomerization.

Shorter-wavelength ultraviolet light is too energetic and would destroy

.

8


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The photoreceptor cells receive light from the back

Free-floating discs

Rhodopsin

Rhodopsin

h

9

h Like Figs.26-5, 26-7


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Each opsin interacts distinctly with retinal, producing a distinct absorption spectrum.

There are 4 opsin paralogs in the human genome.

Absorption spectra of cone pigments

Blue- green- red-

absorbing

10Like Fig. 26-8, 26-9


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Detection of light by retinal bound to opsin

From Darnell et al., Mol. Cell Biology11Like Fig. 26-8


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membrane

from Lecture 12outsideoutside

tsqi

G protein

inside

inside

enzymechannel

effector

cytosol

The usual GPCR pathway cAMPCa2+

intracellular

messenger

nase

phosphorylated

nucleus

12


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membrane

tsqi

G protein

cytosol

enzymechannel

effector

The GPCR pathway in a

ntrace u ar

messenger

Ca2+ cAMPcGMPphotoreceptor

channel

13


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Beginning of the G Protein-Coupled Receptor Pathway

like previous lectures

Neurotransmitter or hormone

binds to receptor

activates

How fast?

100 ms to 10 s

How far?

Probably less 1 m

Effector:enzyme or channel

G protein

outside

inside

GTP GDP + Pi 14


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Special aspects of the G protein-coupled receptor pathway in photoreception

o on somer zesretinal bound to rhodopsin

How fast?

< 100 ms

How far?

< 1 mactivates

G rotein

h

Effector is an enzyme

In rods and cones, these proteins lack lipid tails

cytosol between disks,

or

Although the components

GTP GDP + Pi

are not membrane-bound,the membranes effectively

restrict their motion

15Like Fig. 26-7


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Intracellular messengers bind to proteins

Expanding on a previous lecture, we said . . .

intracellular

messen er

kinases

Ca2+cAMPcGMP

phosphorylated

protein

(olfactory system, retina)

NH2

N

NN

OO

OHO

HHP

-O

cyclic AMP (cAMP)Cyclic nucleotide

(cAMP or cGMP)

16


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Cyclic GMP is the second messenger for phototransduction

High cyclic GMP keeps the

plasma membrane

depolarized and keeps

lutamate release at the

Increased Hydrolysis of cGMP reduces

cGMP concentration, resulting in closing

of a cation channel in the outer segment

membrane and transient

terminal high.

hyperpolarization of the entire plasmamembrane.

17


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like a previous Lecture receptor

G protein

cAMPATP

Effector enzyme

cyclase

tsqi

enzymechannel

effector

Breakdown enzyme

phosphodiesterase

intracellularmessenger

Inhibited by caffeine uninterestingCa2+

ccGMP

cGMPGTP

Enzyme

cyclase

c anne

Breakdown enzyme

phosphodiesterase

A paralog expressed

elsewhere in the body is

inhibited by Viagra

Viagra . . . may cause a

perception of bluish haze or

increased light sensitivity in

uninteresting

The effector for Gt

some pa en s.

18


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Rods and Cones have

cGMP-activated Na+/Ca2+ Channels

like a previous Lecturereceptor

G protein

qi ts

enzymechannel

effector

Excised

inside-out patch

intracellularmessenger

allows access

to the inside surface

of the membrane+cGMP*

Ca2+ccGMP

no channel openings

c anne

open

+cGMP*

closed19


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Light Response of the Photoreceptor Cell

The vertebrate photoreceptor functions electrophysiologically opposite to most.

1. Rhodopsin absorbs light

2. Cation channels close in the plasma membrane of the outer segment, whichhyperpolarizes the entire cell

.

3. The h er olarization rela s visual information to the s na tic terminal

20

where it slows ongoing release of the transmitter glutamate.


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The ribbon synapse facilitates the tonic high rate of transmitter release

Photoreceptor to horizontal cell synapse

21


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The Phototransduction Cascade:

1. Amplification 2. Adaptative/homeostatic mechanisms

1. When fully dark-adapted, many species can detect ~1 photonper photoreceptor cell

2. When fully light-adapted, many species can accurately analyze

light at intensities ~1010 fold brighter

Many adaptive and homeostatic mechanisms underlie these phenomena.

Note: it is incorrect to ex lain that our favorite rocess memor , learnin ,

addiction) occurs because of homeostasis or adaptation.Homeostasis and adaptation are not, by themselves, mechanisms.

.

22


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1. Amplification (2. Adaptive/homeostasic mechanisms)

1a. When the rod is dark adapted, the activated Receptor (O*) can activate

1b. The phosphodiesterase has a turnover number of 4200/sec, near the

diffusion limit for catalysis.

1c. Each millisecond that the cGMP-dependent cation channel in the rod

outer segment plasma membrane is open,10,000 ions flow through it.23


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(1. Amplification) 2. Adaptive/homeostatic mechanisms

a. rans uc n y ro yses o an us nac va es se .

2b. The activated receptor (O* or R*) must also be deactivated.

(1) Rhodopsin kinase phosphorylates the carboxyl tail of the receptor

(2) The phosphorylation permits binding of the inhibitory protein, arrestin

3c. Guanylate cyclase must synthesize new cGMP from GTP

(1) Guanylate cyclase is partially inhibited by [Ca2+] >

~75 nM.

(2) Ca2+

influx through the tonically open cationchannel sets the cytosolic level of Ca2+ to ~ 500 nM.

(3) When the cation channel closes upon light

stimulation, Ca2+ continues to be pumped out via the

usual processes, lowering cytosolic Ca2+ to ~50 nM

and activating guanylate cyclase

24


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3. Neurons of the retina

Glutamate is the major transmitter;

Some neurons make

Rod

Cone

dopamine & acetylcholine.

Inhibitory neurons release GABA.

Many paralogs to genes expressed

elsewhere:

Channels, receptors, transporters.

Synapses of outer plexiform layer

Horizontal cells

Synapses of inner plexiform layer

optic nerve25

Like Fig. 26-2


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Roger Sperrys Nobel prize-winning experiments (1948) (goldfish):

After he cut the o tic nerve individual fibers rew back to their ori inal destination in

4. Connections to the brainA previous Lecture

the brain.

Sperry postulated a

chemoaffinity betweenthe nerves and their target

cells.

Sperry also conducted the Split brain

exper men s a orm e as s or

modern ideas about the distinct

specialties of the two hemispheres.26


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,

but

visual maps arose at least 500 Myr ago.

We will discuss visual maps in the next

lectures.

Horseshoe crabs

(Limulus polyphemus)

27


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Sperrys chemoaffinity

in the retinotectal s stem:

A Normal

Cell bodies Growth cones

Discussed in a previous lecture

tyrosine

kinase peptideEphrins:

-

a 21st Century viewA P A P

Retina Tectum

receptors ligands for

thesereceptors

can induce growth cone

collapse. B Confined overexpression of Ephrin A2

are distributed in gradients

in the retina and tectum.

E h re ulsive si nalin

A P A P

partially defines Sperrys

chemoaffinity that sets

up the retinotectal map.C Inactivate Ephrin A5

Axons with highEph kinase

expression avoid tectal

re ions with hi h

A P A P

28

levels ofephrin

Figs 54-13, 54-14


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Pax-6 / Ey functions when expressed at various locations in Drosophila

5. Master switches for eye development?

Little Alberts 8-25 Garland29


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enormously among

organisms,

yet even a human Pax-6

ortholog induces an eye in

Ey mutant Drosophila!

30


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6. Time frame for evolution of the major structural features

A Pessimistic Estimate Of The Time Required For An Eye To Evolve,

D.-E. Nilsson and S. Pel er

1 2 3 4

Proceedings of the Royal Society London B, 1994, 256, pp. 53-58.

Estimate: several hundred thousand yr from primitive eyespot to fisheye with lens

Selective advantages of the intermediate steps are summarized here:

http://www.pbs.org/wgbh/evolution/library/01/1/l_011_01.html

5 86 731


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Bi / CNS / NB 150

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