Functional signals between cells are received by
transmembrane proteins as signal transmitters.
During evolution, relatively simple precursor
genes for such proteins gave rise to multiple
structurally and functionally related genes.
Their corresponding proteins serve to transmit
ions (sodium, potassium, calcium, chloride, and
others), as neurotransmitters, and for perception
of light and odors, etc. Cloning of these
genes has yielded insight into the variety of
functions of transmembrane signal transmitters.
Their general structure can be traced back
to an evolutionarily conserved ancestral
molecule.
Sunday, April 12, 2009
Transmembrane structure of voltage-gated ion channels
The direct flowof ions across the cell membrane
is regulated by ion channels. The transmembrane
proteins, composed of several domains,
are arranged so that they form pores that can be
opened and closed. The simplest model is the
potassium channel (1). This membrane-bound
polypeptide contains six transmembrane
domains. The amino and the carboxy ends of
the protein lie within the cell. Changes in cell
membrane potential or voltage cause the channel
to open (or close) in order to initiate (or terminate)
a brief flow of ions. Domain 4, which is
composed of polar amino acids, is crucial for the
flow of ions. Sodium and calcium ion channels
consist of four subunits (2) of similar structure,
each resembling a potassium channel. The similarity
is due to the common evolutionary origin
of their genes. The four subunits of the sodium
channel (3) are positioned to form a very narrow
porelike passage, much narrower than a
potassium channel, through the plasma membrane.
Ion transport is brought about by membrane
depolarization
is regulated by ion channels. The transmembrane
proteins, composed of several domains,
are arranged so that they form pores that can be
opened and closed. The simplest model is the
potassium channel (1). This membrane-bound
polypeptide contains six transmembrane
domains. The amino and the carboxy ends of
the protein lie within the cell. Changes in cell
membrane potential or voltage cause the channel
to open (or close) in order to initiate (or terminate)
a brief flow of ions. Domain 4, which is
composed of polar amino acids, is crucial for the
flow of ions. Sodium and calcium ion channels
consist of four subunits (2) of similar structure,
each resembling a potassium channel. The similarity
is due to the common evolutionary origin
of their genes. The four subunits of the sodium
channel (3) are positioned to form a very narrow
porelike passage, much narrower than a
potassium channel, through the plasma membrane.
Ion transport is brought about by membrane
depolarization
Seven-helix structure of transmembrane signal transmitters
Indirect transmission of signals is more
frequent than the direct transport of ions or ligand-
gated impulse transmission. Here, the
transmembrane protein is involved only in the
first step of signal transmission.
frequent than the direct transport of ions or ligand-
gated impulse transmission. Here, the
transmembrane protein is involved only in the
first step of signal transmission.
common structural motif is a transmembrane protein
An especially common structural motif
is a transmembrane protein containing seven !
helices within the plasma membrane. The
amino end is extracellular; the carboxy end is
intracellular. Different oligosaccharide side
chains are usually bound to the extracellular
domains. The intracellular domains have binding
sites for other molecules involved in signal
transmission. The seven-helix motif is the
characteristic structure of G protein-binding receptors
(p. 268). As the G proteins themselves,
these receptors and their genes form a large
family with a long evolutionary history. In
yeast, they serve to discern the pheromones of
the mating types (p. 186); in higher organisms
they are the basis for transmitting signals of vision,
smell, and taste
is a transmembrane protein containing seven !
helices within the plasma membrane. The
amino end is extracellular; the carboxy end is
intracellular. Different oligosaccharide side
chains are usually bound to the extracellular
domains. The intracellular domains have binding
sites for other molecules involved in signal
transmission. The seven-helix motif is the
characteristic structure of G protein-binding receptors
(p. 268). As the G proteins themselves,
these receptors and their genes form a large
family with a long evolutionary history. In
yeast, they serve to discern the pheromones of
the mating types (p. 186); in higher organisms
they are the basis for transmitting signals of vision,
smell, and taste
A receptor with two transmembrane protein chains,
The receptor for "-aminobutyric acid (GABA)
utilizes two transmembrane protein subunits, !
and #. Both the amino and the carboxy ends are
extracellular. The two chains are coded for by
different genes. Several oligosaccharide side
chains are present on the extracellular side. The
# chain contains a phosphorylation site for
cAMP-dependent protein kinase.
utilizes two transmembrane protein subunits, !
and #. Both the amino and the carboxy ends are
extracellular. The two chains are coded for by
different genes. Several oligosaccharide side
chains are present on the extracellular side. The
# chain contains a phosphorylation site for
cAMP-dependent protein kinase.
Receptors of Neurotransmitters
Impulses are relayed between nerve cells or between
nerve and muscle cells by various transmitter
molecules (neurotransmitters). Their effects
are further relayed by receptors in the cell
membrane. Receptors can be differentiated according
to their structure, which in turn determines
their specificity.
nerve and muscle cells by various transmitter
molecules (neurotransmitters). Their effects
are further relayed by receptors in the cell
membrane. Receptors can be differentiated according
to their structure, which in turn determines
their specificity.
Acetylcholine as a neurotransmitter
Cholinergic synapses convey the nerve impulse
from one nerve cell to another or from a nerve
cell to a muscle cell (motor endplate). Acetylcholine
leads to postsynaptic depolarization
through the release of potassium ions (K+) and
the uptake of sodium ions (Na+). This process is
regulated by an acetylcholine receptor.
from one nerve cell to another or from a nerve
cell to a muscle cell (motor endplate). Acetylcholine
leads to postsynaptic depolarization
through the release of potassium ions (K+) and
the uptake of sodium ions (Na+). This process is
regulated by an acetylcholine receptor.
Acetylcholine receptors
The acetylcholine receptors are of two genetically
and functionally different types. Pharmacologically
they can be differentiated according
to the effects of nicotine and muscarine.
The nicotine-sensitive acetylcholine receptor is
an ion channel for potassium and sodium. It
consists of five subunits: two !, one ", one #,
and one $ (1). Acetylcholine binds as a ligand to
the two ! subunits. Each subunit consists of
four transmembrane domains (2). Each subunit
is encoded by its own gene (3). These genes
have similar structures and nucleotide base
sequences. The ligand-gated ion channel is an
example of direct transport without an intermediate
carrier. A mutation in the second transmembrane
region has been shown to change
the ion selectivity from cations to anions
and functionally different types. Pharmacologically
they can be differentiated according
to the effects of nicotine and muscarine.
The nicotine-sensitive acetylcholine receptor is
an ion channel for potassium and sodium. It
consists of five subunits: two !, one ", one #,
and one $ (1). Acetylcholine binds as a ligand to
the two ! subunits. Each subunit consists of
four transmembrane domains (2). Each subunit
is encoded by its own gene (3). These genes
have similar structures and nucleotide base
sequences. The ligand-gated ion channel is an
example of direct transport without an intermediate
carrier. A mutation in the second transmembrane
region has been shown to change
the ion selectivity from cations to anions
The muscarine-sensitive type of acetylcholine
The muscarine-sensitive type of acetylcholine
receptor is a protein that contians seven transmembrane
subunits (4). Since each exists in the
form of an ! helix, it is referred to as a sevenhelix
transmembrane protein (p. 270). The
amino end (NH2) lies extracellularly; the carboxy
end (COOH), intracellularly. The transmembrane
domains are connected by intracellular
and extracellular polypeptide loops (4).
Different domains of the whole protein are distinguished
(5) according to location and the
relative proportion of hydrophilic and hydrophobic
amino acids. The amino end and the carboxy
end each form a domain just like the intracellular
(a–c), and extracellular portions (d–f).
receptor is a protein that contians seven transmembrane
subunits (4). Since each exists in the
form of an ! helix, it is referred to as a sevenhelix
transmembrane protein (p. 270). The
amino end (NH2) lies extracellularly; the carboxy
end (COOH), intracellularly. The transmembrane
domains are connected by intracellular
and extracellular polypeptide loops (4).
Different domains of the whole protein are distinguished
(5) according to location and the
relative proportion of hydrophilic and hydrophobic
amino acids. The amino end and the carboxy
end each form a domain just like the intracellular
(a–c), and extracellular portions (d–f).
The transmembrane domains
The transmembrane domains located within
the plasma membrane (1–7) consist for the
most part of hydrophobic amino acids. The
structure of the gene product corresponds to
the general structure of the gene (6). The different
domains are coded for by individual exons.
The DNA nucleotide sequences within functionally
similar domains are similar.
The seven-helix transmembrane motif occurs
in many receptors. The general structures of the
genes and of the gene products are very similar,
but they differ in their specificity of binding to
other functionally relevant molecules (G proteins).
They play a role not only as neurotransmitters
but also in the transmission of
light, odors, and taste.
the plasma membrane (1–7) consist for the
most part of hydrophobic amino acids. The
structure of the gene product corresponds to
the general structure of the gene (6). The different
domains are coded for by individual exons.
The DNA nucleotide sequences within functionally
similar domains are similar.
The seven-helix transmembrane motif occurs
in many receptors. The general structures of the
genes and of the gene products are very similar,
but they differ in their specificity of binding to
other functionally relevant molecules (G proteins).
They play a role not only as neurotransmitters
but also in the transmission of
light, odors, and taste.
Genetic Defects in Ion Channels
More than 20 different disorders due to defective
ion channel proteins resulting from gene
mutations are known. Such disorders include
cystic fibrosis (see p. 276), the long-QT syndrome,
a special type of deafness, hereditary
hypertension (Liddle syndrome), familial persistant
hyperinsulinemic hypoglycemia of infancy,
some hereditary muscle diseases, and
malignant hyperthermia (see p. 372), among
other disorders.
ion channel proteins resulting from gene
mutations are known. Such disorders include
cystic fibrosis (see p. 276), the long-QT syndrome,
a special type of deafness, hereditary
hypertension (Liddle syndrome), familial persistant
hyperinsulinemic hypoglycemia of infancy,
some hereditary muscle diseases, and
malignant hyperthermia (see p. 372), among
other disorders.
Long-QT syndrome, a genetic cardiac arrhythmia
Congenital long-QT syndrome is characterized
by a prolonged QT interval in the electrocardiogram
(more than 460 ms, corrected for heart
rate), sudden attacks of missed heart beats
(syncopes) or series of rapid heart beats (torsades
de pointes), and an increased risk for sudden
death from ventricular fibrillation in
children and young adults.
by a prolonged QT interval in the electrocardiogram
(more than 460 ms, corrected for heart
rate), sudden attacks of missed heart beats
(syncopes) or series of rapid heart beats (torsades
de pointes), and an increased risk for sudden
death from ventricular fibrillation in
children and young adults.
Different molecular types of long-QT syndrome
Prolongation of the QT interval in the electrocardiogram
results from an increase in the duration
of the cardiac action potential (1). The
normal potential lasts about 300 ms (phases 1
and 2). The resting membrane potential (phase
3) is reached by progressive inactivation of calcium
currents and increasing depletion of
potassium currents, which repolarize the cell.
In phase 0 the cell is quickly depolarized
results from an increase in the duration
of the cardiac action potential (1). The
normal potential lasts about 300 ms (phases 1
and 2). The resting membrane potential (phase
3) is reached by progressive inactivation of calcium
currents and increasing depletion of
potassium currents, which repolarize the cell.
In phase 0 the cell is quickly depolarized
LQT1 accounts
LQT1 accounts for about half of the patients
with long-QT syndrome. The gene for LQT2 encodes
a 1195-amino-acid transmembrane protein
responsible for the other major potassium
channel that participates in phase 3 repolarization
(HERG stands for (human-ether-r-go-gorelated
gene, a Drosophila homologue). LQT3, a
sodium channel protein, consists of four subunits,
each containing six transmembrane
domains and a number of phosphate-binding
sites. Homozygosity for LQT1 (KVLQT1 gene) or
LQT5 (KCNE1 gene) causes a form of long-QT
syndrome associated with deafness, the Jervell
and Lange-Nielsen syndrome. (Figure adapted
from Ackerman and Clapham, 1997.) It is important
to distinguish the different types because
the choice of medication differs.
with long-QT syndrome. The gene for LQT2 encodes
a 1195-amino-acid transmembrane protein
responsible for the other major potassium
channel that participates in phase 3 repolarization
(HERG stands for (human-ether-r-go-gorelated
gene, a Drosophila homologue). LQT3, a
sodium channel protein, consists of four subunits,
each containing six transmembrane
domains and a number of phosphate-binding
sites. Homozygosity for LQT1 (KVLQT1 gene) or
LQT5 (KCNE1 gene) causes a form of long-QT
syndrome associated with deafness, the Jervell
and Lange-Nielsen syndrome. (Figure adapted
from Ackerman and Clapham, 1997.) It is important
to distinguish the different types because
the choice of medication differs.
Chloride Channel Defects: Cystic Fibrosis
Cystic fibrosis (mucoviscidosis) is a highly variable
multisystemic disorder due to mutations of
the cystic fibrosis transmembrane conduction
regulator gene (CFTR). Cystic fibrosis (CF) is one
of the most frequent autosomal recessive
hereditary diseases in populations of European
origin (about 1 in 2500 newborns). The high
frequency of heterozygotes (1:25) is thought to
result from their selective advantage due to reduced
liability to epidemic diarrhea (cholera).
multisystemic disorder due to mutations of
the cystic fibrosis transmembrane conduction
regulator gene (CFTR). Cystic fibrosis (CF) is one
of the most frequent autosomal recessive
hereditary diseases in populations of European
origin (about 1 in 2500 newborns). The high
frequency of heterozygotes (1:25) is thought to
result from their selective advantage due to reduced
liability to epidemic diarrhea (cholera).
Cystic fibrosis: clinical aspects
The disease primarily affects the bronchial system
and the gastrointestinal tract. Viscous
mucus formation leading to frequent, recurrent
bronchopulmonic infections and eventually
chronic oxygen deficiency characterize the
common, severe form of the disease. The average
life expectancy in typical CF is about 30
years. The diseasemay take a less severe, almost
mild course. Congenital bilateral absence of the
vas deferens (CBAVD) occurs in 95% of patients
with CF. It may be the only manifestation in individuals
with different mutant allelic combinations
at the CF locus.
and the gastrointestinal tract. Viscous
mucus formation leading to frequent, recurrent
bronchopulmonic infections and eventually
chronic oxygen deficiency characterize the
common, severe form of the disease. The average
life expectancy in typical CF is about 30
years. The diseasemay take a less severe, almost
mild course. Congenital bilateral absence of the
vas deferens (CBAVD) occurs in 95% of patients
with CF. It may be the only manifestation in individuals
with different mutant allelic combinations
at the CF locus.
cystic fibrosis (CF)
Positional cloning of the gene for
The CFTR gene was isolated on the basis of its
chromosomal location (positional cloning) on
the long arm of chromosome 7 at q31 (7q31).
Since the gene could be mapped to the long arm
of chromosome 7 near a marker locus D7S15, a
long-range restriction map comprising about
1500 kb containing the presumptive CF locus
flanked by two marker loci, MET and D7S8, was
constructed. From there a region of 250 kb was
isolated by a combination of chromosome
walking and chromosome jumping. Several
genes were located in this region (candidate
genes) between the marker loci D7S340 and
D7S424. The gene sought was identified by the
finding of mutations of this gene in patients but
not in controls, by comparing with similar
genes in other organisms (evolutionary conservation),
by determining its exon/intron structure,
by sequencing it, and by determining the
expression pattern of the gene in different tissues.
The CFTR gene was isolated on the basis of its
chromosomal location (positional cloning) on
the long arm of chromosome 7 at q31 (7q31).
Since the gene could be mapped to the long arm
of chromosome 7 near a marker locus D7S15, a
long-range restriction map comprising about
1500 kb containing the presumptive CF locus
flanked by two marker loci, MET and D7S8, was
constructed. From there a region of 250 kb was
isolated by a combination of chromosome
walking and chromosome jumping. Several
genes were located in this region (candidate
genes) between the marker loci D7S340 and
D7S424. The gene sought was identified by the
finding of mutations of this gene in patients but
not in controls, by comparing with similar
genes in other organisms (evolutionary conservation),
by determining its exon/intron structure,
by sequencing it, and by determining the
expression pattern of the gene in different tissues.
The CFTR gene and its protein
The CFTR gene is large, extending over 250 kb of
genomic DNA, and is organized into 27 exons
(24 are shown in the diagram) encoding a 6.5 kb
transcript with several alternatively spliced
forms of mRNA. The CFTR protein has 1480
amino acids. It is a membrane-bound chloride
ion channel regulator with several functional
domains: two nucleotide-binding domains (encoded
by exons 9–12 and 19–23), a regulatory
domain (exons 12–14a), and two transmembrane-
spanning domains (exons 3–7 and 14b–
18). Each of the two transmembrane regions
consists of six transmembrane segments. The
nucleotide-binding domain 1 (NBD1) confers
cAMP-regulated chloride channel activity. The
most common mutation (occurring in 66% of
patients), a deletion of a phenylalanine codon in
position 508 (!F508), is located here. The protein
is a member of the ATP-binding cassette
(ABC) family of transporters. The R domain contains
putative sites for protein kinase A and protein
kinase C phosphorylation. CFTR is widely
expressed in epithelial cells.
genomic DNA, and is organized into 27 exons
(24 are shown in the diagram) encoding a 6.5 kb
transcript with several alternatively spliced
forms of mRNA. The CFTR protein has 1480
amino acids. It is a membrane-bound chloride
ion channel regulator with several functional
domains: two nucleotide-binding domains (encoded
by exons 9–12 and 19–23), a regulatory
domain (exons 12–14a), and two transmembrane-
spanning domains (exons 3–7 and 14b–
18). Each of the two transmembrane regions
consists of six transmembrane segments. The
nucleotide-binding domain 1 (NBD1) confers
cAMP-regulated chloride channel activity. The
most common mutation (occurring in 66% of
patients), a deletion of a phenylalanine codon in
position 508 (!F508), is located here. The protein
is a member of the ATP-binding cassette
(ABC) family of transporters. The R domain contains
putative sites for protein kinase A and protein
kinase C phosphorylation. CFTR is widely
expressed in epithelial cells.
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