OUR 5 MAJOR SENSORY SYSTEMS

Vision - the detection of light

Olfaction- (sense of smell) the detection of small molecules in the air

Taste or Gustation- the detection of selected organic compounds and ions by the tongue

Hearing-The detection of sound (or pressure wave in the air)

Touch- the detection of changes in pressure, temp. and other factors by the skin

S E N S O R Y S Y S T E M S

When fully adapted to darkness our eyes allow us to sense very low levels of light, down to a limit of less than 10 photons.

With more light we are able to distinguish millions of colors.

Through our senses of smell and taste we are able to detect thousands of chemicals

and sort them into distinct categories

Each of these primary sensory systems contains specialized sensory neurons that transmit nerve

impulses to the CNS

In the CNS theses signals are processed and combined with other information to

yield a perception that may trigger a change in behavior.

By these means, our senses allow us to detect changes in our environments and

adjust our behavior appropriately

Vision is based on the absorption of light by photoreceptor cells in the eye

Photoreceptor cells are sensitive to light in a relativelynarrow region of the electromagnetic spectrum between 300-850nm

Photoreceptor molecules in the eye

detect visible light

Two kinds of photoreceptorsRods (100 million) and Cons (3 million)Rods function in dim light and do not perceive colorCons function in bright light and are responsible for color vision

VISIONPigment epithelium

Neuronal layers

The Retina• Contains photoreceptor cells (rods

and cones) and associated interneurones and sensory neurones

light

to opticnerve

ganglioncells

bipolarneurones

rodcells

conecells

pigmentedretina

Vision---rod/cones-The incoming light reaches the photoreceptor cells (rods and cones) only after passing through several thin, transparent layers of other neurons. -The pigment epithelium absorbs the light that is not absorbed by the photoreceptor cells and thus minimizes reflections of stray light.

The ganglion cells communicate to the thalamus by sending action potentials down their axons.

However, the photoreceptor cells and other neurons communicate by graded synaptic potentials that are conducted electronically.

The neural circuits in the retinaThe neural circuits in the retina of a primateof a primate

The Rod Cell

Scanning electron micrographs of retinal rod cells

Schematic representation of a rod cell

Biochemistry. L. Stryer

(1x40µm)

100,000,000 rod cellsin human retina

Photoperception

1000 disks, 16nm thick

Rod cell

The disks which are membrane enclosed sacs are densely packed with photoreceptor molecules

The photosensitive molecule is called the visual pigment because it is highly colored due to light absorption

The photoreceptor molecule in the rods is rhodopsinconsists of opsin linked to 11-cis-retinal

The electromagnetic spectrum300-850nm

Absorption spectrum of rhodopsinAbsorption spectrum of rhodopsin

Questions

How does the cell respond to How does the cell respond to photons?photons?

What mechanism converts light What mechanism converts light into a cellular signal?into a cellular signal?

Rhodopsin

Ligand-activated Receptor

Light-activated Receptor

(polyene- with 6 alternating double and single bonds)

Illustration of Rhodopsin (blue)with11-cis retinal (red)

The protonated form of the 11-cis retinal absorbs at 440nmUnlike 380nm of the non-protonated.The positive charge of Lys296(VII) is compensated by Glu113(II)

(440nm absorption)

Activation of rhodopsin by a photon-converting a light energy of A photon into atomic motion

-The isomerization causes the Shiff-base nitrogen to moveapproximately 5A, assuming that the cyclohexane ring of the cis-retinal group remains fixed/-Inverse agonist--Inverse agonist- 108 Rhodopsin molecules /cell

Cys 110Cys 187 Lys 296

Glu113

OutOut

InIn

Asp2

Asp15

Glu181

Met1

Cys322Cys323

D(E)RY

Helix VIII (311-321)

RHODOPSINRHODOPSIN

Rhodopsin 2.8A resolution; Science 389,739 (2000)

Science 289, 739-745 (2000)

The three dimensional structure of rhodopsin

PalmitoylPalmitoylat Helix 8at Helix 8

Retinal

Three dimensional Model of Rhodopsin

Alcohol dehydrogenases

Rhodopsin photoactivation

Transducin Transducin t 39kD; 36kD; 8kD

In the dark transducin is in the GDP formthe binding of GTP to transducin leads to therelease of R* which enables it to catalyze theActivation of another molecule of transducin

A single R* catalyzes the activation of 500molecules of transducin, the first stage in the amplification of vision

Schematic diagram of the cyclic GMP cascade of vision

The binding of GTP switches on the phosphodiesterase (PDE) by relieving an inhibitory constraint. In the dark the two catalytic subunits and are held in check by a pair of

inhibitory subunits ().By binding of Gt to the enzyme it removes the inhibitory

subunits and the enzyme is activated

Activation of phosphodiesterase

by Gt

Gt

GtGt

Inactive Active

The hydrolysis of cGMP by phosphodiesterase is the second stage of of amplification

11-cis-retinal 11-trans-retinal

mV

Mem

bran

e po

tent

ial

Light hyperpolarizes the plasma membrane of a retinal rod cell

The light induced hyperpolarization is transmitted by the plasmamembrane from the outer segment to the synaptic body.A single photon closes hundreds of cation specific channels (~500)and leads to a hyperpolarization of about 1-5mV

Cation channels (~500) in the rod cell close following the transduction of a

single photon.

These represent 3% of the total number of channels that are open in the dark. The resultant hyperpolarization is about 1mV

and lasts about 1 sec.

This is sufficient to depress the rate of neurotransmitter release that transmits

the onward signal

The high-degree of co-operativity (3 molecules of cGMP) to open the channel increases the sensitivity of the channel for small changes in cGMP which enable it to act as a switch.

CNG- Cyclic nucleotide-gated channelsCNG- Cyclic nucleotide-gated channels

Cyclic nucleotide binding domain

Dark Current

In the Dark…

• In the dark the channel is open Na+ flow in can cause rod cells to depolarise.– Therefore in total darkness, the membrane of a rod cell is

polarised

• Therefore rod cells release neurotransmitter in the dark

• However the synapse with bipolar cells is an inhibitory synapse i.e. the neurotransmitter stops impulse

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BiologyMad.com

In the Light…

As cis retinal is converted to trans retinal, the Na+ channels begin to close

less neurotransmitter is produced. If the threshold is reached, the bipolar cell will be

depolarised

forms an impulse which is then passed to the ganglion cells and then to the brain

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BiologyMad.com

Rods and ConesRods Cones

Outer segment is rod shaped

Outer segment is cons shaped

109 cells per eye, distributed throughout the retina, so used for peripheral vision.

106 cells per eye, found mainly in the fovea, so can only detect images in centre of retina.

Good sensitivity Poor sensitivity

Only 1 type monochromatic vision

3 types (R, G & B) colour vision

Many rods connected to one bipolar cell poor acuity = poor resolution

Each cone is connected to one bipolar cell good acuity = good resolution

BiologyMad.com

One rhodopsin molecule Absorbs one photon

500 Transducin molecules are activated

500 Phospodiesterase moleculesare activated

105 cGMP molecules are hydrolyzed

250 Na+ channels closed

106-107 ions/sec are prevented from entering the cell for a period of 1 sec

Rod cell membrane is hyperpolarized by 1 mV

GTP cGMP +PPi

Guanylate cyclase

The enzyme Guanylate cyclase looses its activity in high Ca2+

Color Vision

• 3 different cone cells. Each have a different form of opsin (they have the same retinal)

• 3 forms of rhodopsin are sensitive to different parts of the spectrum– 10% red cones – 45% blue cones – 45% blue cones

BiologyMad.com

The absorption spectra of the cone visual pigment responsible for color vision

The cone photoreceptors are 7TM domain receptors that utilize 11-cis-retinal as chromophore. Absorption maxima (nm) in human are 426 (blueblue), 530 (greengreen) and 560560 (redred)

Con CellsCon Cells

Comparison of the amino acid sequence of the green and red photoreceptors

• Colored light will stimulate these 3 cells differently - by comparing the nerve impulses from the 3 kinds of cones the brain can detect any colour– Red light stimulates R cones– Yellow light stimulates R and G cones equally– Cyan light stimulates B and G cones equally– White light stimulates all 3 cones equally

• Called the trichromatic theory of color vision

Color Vision

• When we look at something the image falls on the fovea and we see it in color and sharp detail.

• Objects in the periphery of our field of view are not seen in colour, or detail.

• The fovea has high density of cones.

• Each cone has a synapse with one bipolar cell and one ganglion each cone sends impulses to the brain about its own small area of the retina high visual acuity

Color Vision

Evolutionary relationships among visual pigmentsEvolutionary relationships among visual pigments

Visual pigments have evolved by gene duplication

Color blindnessColor blindness

The genes for the greengreen and redred pigments lie adjacent on the human X chromosome. Are 98% identical in nucleotide sequence

including introns and UTR

-Therefore, are susceptible for to unequal homologous recombination

-5% of males have this form of blindness

Recombination pathways leading to color blindness

Rearrangements in the course of DNA replicationA) Loss of visual pigment B) The formation of hybrid pigemnt genes that encode photoreceptors with anomalous abs. spectra

A homologous recombination: the exchange of DNA segment at equivalent positions between chromosomes with substantial similarity

Termination of the signalTermination of the signal

One of the most important part of the signaling machineryis termination of the signal even in the presence of the stimulus

This phenomenon is referred to as “desensitization”“desensitization”

Such mechanisms operate at both the level of the receptor as well as down stream at the level of G-protein

Rapid termination of the receptor signal is controlledby receptor phosphorylation which is mediated by secondmessenger-kinases PKA and PKC or by a distinct Receptor-kinsases (GRKs) together with arrestins

Second-messenger kinase regulationSecond-messenger kinase regulation

PKA and PKC uncouple receptors from their respective G-proteins and serve as negative-feed-back regulatory loops.

Feed back regulation by the 2nd messenger-stimulated kinases PKA and PKC.

The phosphorylated receptor changes its conformation and no longer can activate the G-proteins. It is an agonist non-specific desensitization

Heterologous desensitizationHeterologous desensitization

Homologous desensitizationGRK(G-ptrotein-receptor kinase)-mediated desensitization(G-ptrotein-receptor kinase)-mediated desensitization

A complex mechanism for regulating 7TM-receptor activity called GRK-arrestin system

It is also called an agonist-specific desensitization because only the activated agonist-occupied conformation of the receptor is phosphorylated by by GRK. A two step process in which agonist-occupied receptor is phosphorylated by GRK and then binds an arrestinarrestin proteins. This leads to a rapid-agonist specific desensitization

Heterogous and homologous desensitization

The major GPCR regulatory pathway

involves phosphorylationphosphorylation of activated

receptors by G protein–coupled G protein–coupled

receptor kinases (GRKs),receptor kinases (GRKs),

followed by binding of arrestinarrestin proteins,

which

1) prevent receptors from activating

downstream heterotrimeric G protein

pathways while

2) allowing activation of arrestin-

dependent signaling pathways.

GRK - GRK - G-protein–coupled receptor kinaseG-protein–coupled receptor kinase

As long as the agonist remains bound to the receptor, the activated receptor can continue to activate G proteins.

GRK which is catalytically activated by this interaction, also recognizes the activated conformation of the receptor.

Activated GRKs phosphorylate (P) intracellular domains of the receptor and are then released. The agonist-activated, GRK-phosphorylated receptor binds tightly to an arrestinarrestin protein, which desensitizesdesensitizes further G protein activation and couples the receptor to the clathrin-coated-pit internalization pathway and to arrestin-scaffolded (and G protein–independent) signaling pathways.

GRK-GPCR-kinaseGRK-GPCR-kinaseThe role of GRK-phosphorylation of the receptors in the sequestration process is to facilitate arrestin binding

Experiments to prove this idea

1)A mutated -adrenergic receptor Y326A is a poor

substrate for -Adrenergic receptor-kinase, and is not sequestered. Over-expression of -arrestin restores sequestration

2) Removal of C-terminal tail (sites for GRK sites) prevents sequestration

ArrestinsArrestinsThe arrestin family includes > 6 members several of which undergo alternative splicing

The affinity of -arrestin (selective for the -receptors) increases 10-30 fold by GRK-catalyzed phosphorylation, whereas agonist occupancy has a much less significant effect.

The -arrestins promote internalization by binding to clatherin

Science, 297, 529 (2002)

Rhodopsin

ark

Rhodopsin kinase

adrenergic receptor

PKA

PKA

Homologous desensitizationHomologous desensitization

ActivationTermination

RGS and GAP Activities

Neuron 20, 11-14 (1999)

GTP

GDP

GTP

GDP

11-11-ciscis vs. all- vs. all-transtrans retinal retinal