The human retina contains about 110 million
rod cells for vision in the dark and 6 million
cone cells for color vision in the light. These
cells contain photoreceptors that convert light
into a nerve impulse. Rhodopsin is the photoreceptor
for weak light. The light-transmitting
system consists of numerous components
coded for by genes that are similar in structure
and function to genes for other transmembrane
signal-transmitting molecules.
Sunday, April 12, 2009
A. Rod cells
A rod cell consists of an outer segment with a
photoreceptor region and an inner segment
comprising cell nucleus and cytoplasm with endoplasmic
reticulum, Golgi apparatus, and mitochondria.
The outer segment contains about
1000 disks with rhodopsin molecules in the
membrane. In the periphery, the approximately
16nm thick disks are folded by the protein peripherin.
photoreceptor region and an inner segment
comprising cell nucleus and cytoplasm with endoplasmic
reticulum, Golgi apparatus, and mitochondria.
The outer segment contains about
1000 disks with rhodopsin molecules in the
membrane. In the periphery, the approximately
16nm thick disks are folded by the protein peripherin.
Photoactivation
In 1958, George Wald and co-workers discovered
that light isomerizes 11-cis-retinal (1)
very rapidly into all-trans-retinal (2), a form
that practically does not exist in the dark
(!1 molecule/1000 years). The light-induced
structural change is so great that the resulting
atomic motion can trigger a reliable and reproducible
nerve impulse. The absorption spectrum
of rhodopsin (3) corresponds to the spectrum
of sunlight, with an optimum at a
wavelength of 500 nm. Although vertebrates,
arthropods, and mollusks have anatomically
quite different types of eyes, all three phyla use
11-cis-retinal for photoactivation.
that light isomerizes 11-cis-retinal (1)
very rapidly into all-trans-retinal (2), a form
that practically does not exist in the dark
(!1 molecule/1000 years). The light-induced
structural change is so great that the resulting
atomic motion can trigger a reliable and reproducible
nerve impulse. The absorption spectrum
of rhodopsin (3) corresponds to the spectrum
of sunlight, with an optimum at a
wavelength of 500 nm. Although vertebrates,
arthropods, and mollusks have anatomically
quite different types of eyes, all three phyla use
11-cis-retinal for photoactivation.
Light cascade
Photoactivated rhodopsin triggers a series of
enzymatic steps (light cascade). First, a signaltransmitting
protein of visualization, transducin,
is activated by photoactivated rhodopsin.
Transducin belongs to the G protein family, i.e.,
it can assume an inactive GDP and an active GTP
form. GTP activates phosphodiesterase. This
very rapidly hydrolyzes cGMP and lowers the
cGMP concentration in cytosol, which leads to
closure of the sodium ion channels. Immediately
thereafter, phosphodiesterase is inactivated
by means of a G protein cycle.
enzymatic steps (light cascade). First, a signaltransmitting
protein of visualization, transducin,
is activated by photoactivated rhodopsin.
Transducin belongs to the G protein family, i.e.,
it can assume an inactive GDP and an active GTP
form. GTP activates phosphodiesterase. This
very rapidly hydrolyzes cGMP and lowers the
cGMP concentration in cytosol, which leads to
closure of the sodium ion channels. Immediately
thereafter, phosphodiesterase is inactivated
by means of a G protein cycle.
Rhodopsin
Rhodopsin is a seven-helix transmembrane
protein with binding sites for functionally important
molecules such as transducin, rhodopsin
kinase, and arrestin on the cytosol side. The
binding site of the light-sensitive molecule
(chromophore) is lysine in position 296 of the
seventh transmembrane domain. The light-absorbing
group consists of 11-cis-retinal. The
amino end of rhodopsin is located in the disk interspaces,
and the carboxy end on the cytosol
side. About half of the molecule is contained in
the seven transmembrane hydrophobic domains,
one-fourth in the disk interspaces and
one-fourth on the cytosol side.
protein with binding sites for functionally important
molecules such as transducin, rhodopsin
kinase, and arrestin on the cytosol side. The
binding site of the light-sensitive molecule
(chromophore) is lysine in position 296 of the
seventh transmembrane domain. The light-absorbing
group consists of 11-cis-retinal. The
amino end of rhodopsin is located in the disk interspaces,
and the carboxy end on the cytosol
side. About half of the molecule is contained in
the seven transmembrane hydrophobic domains,
one-fourth in the disk interspaces and
one-fourth on the cytosol side.
cGMP as transmitter in the vizualization process
The light cascade ends with rapid hydrolysis of
cGMP, the internal transmitter in visualization.
This leads to rapid closure of the sodium ion
channels and hyperpolarization of the membrane
to initiate nerve impulse, which is transmitted
as a signal to the brain.
cGMP, the internal transmitter in visualization.
This leads to rapid closure of the sodium ion
channels and hyperpolarization of the membrane
to initiate nerve impulse, which is transmitted
as a signal to the brain.
Mutations in Rhodopsin
Retinitis pigmentosa (RP) is a genetically heterogeneous
group of diseases that lead to
pigmental degeneration of the retina and progressive
blindness. Numerous mutations in the
rhodopsin gene have been shown to be the
cause of different forms of RP. Mutations in
other genes coding for proteins of the light cascade
may also cause retinitis pigmentosa.
group of diseases that lead to
pigmental degeneration of the retina and progressive
blindness. Numerous mutations in the
rhodopsin gene have been shown to be the
cause of different forms of RP. Mutations in
other genes coding for proteins of the light cascade
may also cause retinitis pigmentosa.
Retinitis pigmentosa
The fundus of the eye shows distinct displacement
of pigmentation, with irregular hyperpigmentation
and depigmentation. The papilla
(optic disk) shows waxy yellow discoloration.
The loss of vision, especially in dim light (night
blindness), proceeds from the periphery to the
center at different rates depending on the form
of the disease, until only a very narrow central
visual field remains.
of pigmentation, with irregular hyperpigmentation
and depigmentation. The papilla
(optic disk) shows waxy yellow discoloration.
The loss of vision, especially in dim light (night
blindness), proceeds from the periphery to the
center at different rates depending on the form
of the disease, until only a very narrow central
visual field remains.
Point mutation in codon 23
The first point mutation demonstrated in the
rhodopsin gene (Dryja et al., 1990) was a transversion
from cytosine to adenine in codon
23. This changed the codon CCC for proline (Pro)
into CAC for histidine (His). Since the proline in
position 23 occurs in more than ten related G
protein receptors, it must be very important for
normal function.
rhodopsin gene (Dryja et al., 1990) was a transversion
from cytosine to adenine in codon
23. This changed the codon CCC for proline (Pro)
into CAC for histidine (His). Since the proline in
position 23 occurs in more than ten related G
protein receptors, it must be very important for
normal function.
Mutations in rhodopsin
The gene locus for rhodopsin (RHO) in man lies
on the long arm of chromosome 3 in region 2,
band 1.4 (3q21.4). Dominant and autosomal recessive
inherited mutations have been demonstrated
in humans. Most mutations lead to the
exchange of an amino acid, although deletions
may also occur. Of the 348 amino acids of
rhodopsin, 38 are identical (invariant) at
various positions in vertebrates. More than 100
different mutations are known for autosomal
dominant inherited RP. An increasing number
of mutations are recognized to cause autosomal
recessive RP. In addition, mutations in several
other gene loci have been recognized to lead to
retinitis pigmentosa, e. g. mutations in the gene
for peripherin on the short arm of chromosome
6 in humans (6p) and a locus in the centromeric
region of chromosome 8. Other photoreceptor
gene disease loci are the ! and " subunits of
phosphodiesterase (PDE).
on the long arm of chromosome 3 in region 2,
band 1.4 (3q21.4). Dominant and autosomal recessive
inherited mutations have been demonstrated
in humans. Most mutations lead to the
exchange of an amino acid, although deletions
may also occur. Of the 348 amino acids of
rhodopsin, 38 are identical (invariant) at
various positions in vertebrates. More than 100
different mutations are known for autosomal
dominant inherited RP. An increasing number
of mutations are recognized to cause autosomal
recessive RP. In addition, mutations in several
other gene loci have been recognized to lead to
retinitis pigmentosa, e. g. mutations in the gene
for peripherin on the short arm of chromosome
6 in humans (6p) and a locus in the centromeric
region of chromosome 8. Other photoreceptor
gene disease loci are the ! and " subunits of
phosphodiesterase (PDE).
Demonstration of a mutation in codon 23 by means of oligonucleotides after PCR
This pedigree (1) with autosomal dominant inherited
retinitis pigmentosa due to mutation in
codon 23 includes 13 affected individuals in
three generations (affected females, black
circles; affected males, black squares). Using
polymerase chain reaction (PCR) (see p. 166),
Dryja et al. (1990) demonstrated the mutation
in amplified fragments of exon 1 (2). The normal
oligonucleotide corresponds to the normal
sequence between codons 26 and 20. The mutant
sequence of the oligomere RP contains the
mutant sequence CAC. All affected individuals
gave a hybridization signal
retinitis pigmentosa due to mutation in
codon 23 includes 13 affected individuals in
three generations (affected females, black
circles; affected males, black squares). Using
polymerase chain reaction (PCR) (see p. 166),
Dryja et al. (1990) demonstrated the mutation
in amplified fragments of exon 1 (2). The normal
oligonucleotide corresponds to the normal
sequence between codons 26 and 20. The mutant
sequence of the oligomere RP contains the
mutant sequence CAC. All affected individuals
gave a hybridization signal
Color Vision
As suggested by Thomas Young in 1802, color
vision in humans is mediated by three receptor
types in the cone cells of the retina, one each for
blue, green, and red.
vision in humans is mediated by three receptor
types in the cone cells of the retina, one each for
blue, green, and red.
Genes for photoreceptor proteins in cones
The gene for the blue receptor is autosomal; the
genes for the red and green receptors are X
chromosomal. The absorption spectra of the
three receptors show maxima of 426 nm for
blue, about 530 for green, and about 550 for red.
The red receptorwas discovered to be polymorphic,
with two somewhat different absorption
maxima at 552 and 557 nm.
genes for the red and green receptors are X
chromosomal. The absorption spectra of the
three receptors show maxima of 426 nm for
blue, about 530 for green, and about 550 for red.
The red receptorwas discovered to be polymorphic,
with two somewhat different absorption
maxima at 552 and 557 nm.
Evolution of the genes for visual pigment photoreceptors
The photoreceptor genes arose froma single ancestral
gene (protogene). The rhodopsin–transducin
pair is found in invertebrates and is at
least 700 million years old. The blue receptor is
almost as old as rhodopsin, about 500 million
years. The separation into a receptor for green
and one for red must have occurred only about
30 million years ago, after the Old World and
New World apes separated, since man and the
Old World apes have three cone pigments
whereas NewWorld apes have two.
gene (protogene). The rhodopsin–transducin
pair is found in invertebrates and is at
least 700 million years old. The blue receptor is
almost as old as rhodopsin, about 500 million
years. The separation into a receptor for green
and one for red must have occurred only about
30 million years ago, after the Old World and
New World apes separated, since man and the
Old World apes have three cone pigments
whereas NewWorld apes have two.
Structural similarity of the visual pigments
In 1986, J. Nathans and co-workers sequenced
the genes for color photoreceptors and observed
marked structural similarities, especially
of the green and red receptor genes.
Here the gene products (the receptors) are
shown and their similarities are compared. The
dark dots indicate variant amino acids; the light
dots are identical amino acids, given in percentages.
the genes for color photoreceptors and observed
marked structural similarities, especially
of the green and red receptor genes.
Here the gene products (the receptors) are
shown and their similarities are compared. The
dark dots indicate variant amino acids; the light
dots are identical amino acids, given in percentages.
Polymorphism in the photoreceptor for red
A. G. Motulsky and co-workers (Winderickx et
al., 1992) demonstrated variant codons in three
regions of the red receptor gene (1). Serine was
found at position 180 in 60% of the investigated
males; alanine in 40%. Position 230 showed
polymorphism of isoleucine (Ile) and threonine
(Thr); position 233 of alanine (Ala) and serine
al., 1992) demonstrated variant codons in three
regions of the red receptor gene (1). Serine was
found at position 180 in 60% of the investigated
males; alanine in 40%. Position 230 showed
polymorphism of isoleucine (Ile) and threonine
(Thr); position 233 of alanine (Ala) and serine
Normal and defective red–green vision
One gene for red and one to three genes for
green lie close together on the long arm of the X
chromosome in humans (1). Since the
sequences of these genes are very similar, unequal
crossing-over is not infrequent (2). Intergenic
crossing-over leads to loss (green blindness)
or duplication; intragenic crossing-over
leads to a hybrid gene (red blindness). Green
blindness results from loss of a gene for the
green receptor; red blindness, from a defective
or absent red receptor. With red–green blindness,
neither a normal red nor a normal green
receptor is present. About 1% of all men are red–
green blind and about 2% are green blind. About
8% show weakness in differentiating red from
green.
green lie close together on the long arm of the X
chromosome in humans (1). Since the
sequences of these genes are very similar, unequal
crossing-over is not infrequent (2). Intergenic
crossing-over leads to loss (green blindness)
or duplication; intragenic crossing-over
leads to a hybrid gene (red blindness). Green
blindness results from loss of a gene for the
green receptor; red blindness, from a defective
or absent red receptor. With red–green blindness,
neither a normal red nor a normal green
receptor is present. About 1% of all men are red–
green blind and about 2% are green blind. About
8% show weakness in differentiating red from
green.
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