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)
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
Photoreceptor molecules in the eye
Vision is based on the absorption of light by photoreceptor
cells in the eye
Photoreceptor cells are sensitive to light in a relatively
narrow region of the electromagnetic spectrum between
Two kinds of photoreceptors
Rods (100 million) and Cons (3 million)
Rods function in dim light and do not perceive color
Cons function in bright light and are responsible for color vision
The neural circuits in the retina
of a primate
-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 Rod Cell
Scanning electron micrographs of retinal rod cells
of a rod cell
1000 disks, 16nm thick
100,000,000 rod cells
in human retina
Biochemistry. L. Stryer
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
The photoreceptor molecule in the rods is rhodopsin
consists of opsin linked to 11-cis-retinal
The electromagnetic spectrum
Absorption spectrum of rhodopsin
How does the cell respond to photons?
What mechanism converts light into a cellular signal?
(polyene- with 6 alternating double and single bonds)
11-cis retinal (red)
The protonated form of the 11-cis retinal absorbs at 440nm
Unlike 380nm of the non-protonated.
The positive charge of Lys296(VII) is compensated by Glu113(II)
Activation of rhodopsin by a photon-converting a light energy of
A photon into atomic motion
-The isomerization causes the Shiff-base nitrogen to move
approximately 5A, assuming that the cyclohexane ring
of the cis-retinal group remains fixed/
-Inverse agonist- 108 Rhodopsin molecules /cell
The three dimensional structure of rhodopsin
Rhodopsin 2.8A resolution; Science 389,739 (2000)
Science289, 739-745 (2000)
Three dimensional Model of Rhodopsin
at Helix 8
Transducin at 39kD; b 36kD; 8kD
In the dark transducin is in the GDP form
the binding of GTP to transducin leads to the
release of R* which enables it to catalyze the
Activation of another molecule of transducin
A single R* catalyzes the activation of 500
molecules 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 subunitsa and b are held in check by a pair of inhibitory subunits (g).By binding of Gat to the enzyme it removes the inhibitory subunits and the enzyme is activated
Activation of phosphodiesterase
The hydrolysis of cGMP by phosphodiesterase is the second stage of
Light hyperpolarizes the plasma membrane of a retinal rod cell
The light induced hyperpolarization is transmitted by the plasma
membrane 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 channels
As cis retinal is converted to trans retinal, the Na+ channels begin to closei
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
Absorbs one photon
500Transducin molecules are activated
105 cGMP molecules are hydrolyzed
250Na+ channels closed
106-107ions/sec are prevented from entering
the cell for a period of 1 sec
Rod cell membrane is
hyperpolarized by 1 mV
GTP cGMP +PPi
The enzyme Guanylate cyclase
looses its activity in high Ca2+
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 (blue), 530 (green) and 560 (red)
Comparison of the amino acid sequence of
the green and red photoreceptors
Evolutionary relationships among visual pigments
Visual pigments have evolved by gene duplication
The genes for the green and red 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 replication
A) 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 signal
One of the most important part of the signaling machinery
is termination of the signal even in the presence of the stimulus
This phenomenon is referred to as “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 controlled
by receptor phosphorylation which is mediated by second
messenger-kinases PKA and PKC or by a distinct
Receptor-kinsases (GRKs) together with arrestins
Second-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
Homologous desensitizationGRK(G-ptrotein-receptor kinase)-mediated desensitizationA complex mechanism for regulating 7TM-receptor activity called GRK-barrestin systemIt 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 arrestin proteins. This leads to a rapid-agonist specific desensitization
Heterogous and homologous desensitization
The major GPCR regulatory pathway involves phosphorylation of activated receptors by G protein–coupled receptor kinases (GRKs),
followed by binding of arrestin proteins, which
prevent receptors from activating downstream heterotrimeric G protein pathways while
allowing activation of arrestin-dependent signaling pathways.
GRK - G-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 arrestin protein, which desensitizes 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.
The role of GRK-phosphorylation of the receptors in the sequestration process is to facilitate arrestin binding
Experiments to prove this idea
1)A mutated b-adrenergic receptor Y326A is a poor
substrate for b-Adrenergic receptor-kinase, and is not sequestered. Over-expression of b-arrestin restores sequestration
2)Removal of C-terminal tail (sites for GRK sites) prevents sequestration
The arrestin family includes > 6 members several of which undergo alternative splicing
The affinity of b-arrestin (selective for the b-receptors) increases 10-30 fold by GRK-catalyzed phosphorylation, whereas agonist occupancy has a much less significant effect.
The b-arrestins promote internalization by binding to clatherin
Science, 297, 529 (2002)
RGS and GAP Activities
Neuron 20, 11-14 (1999)
11-cis vs. all-trans retinal