Human beings belong to the family of Hominidae.
Within this family they are a single
living species, Homo sapiens. Studies of DNA
sequences obtained from different parts of the
human genome from populations living in
different regions of the world indicate that the
genetic diversity of humans living today is surprisingly
limited. The origin of today’s humans
can be traced back to about 100000 to 300000
years ago in Africa. From here, an anatomically
modern H. sapiens ancestor spread out over the
earth and diversified. About 90% of the overall
genetic variation in humans is among individuals
and only 10% among different ethnic groups.
There are no races of H. sapiens; rather, different
ethnic groups have developed in different
geographic regions during the past 30000–
40000 years
Sunday, April 12, 2009
Hominid family tree with uncertain relationships
The oldest identified hominid skeletal remains
have been found in Eastern Africa. They are attributed
to an extinct genus, Australopithecus.
Several different species originated about 4.5 to
2 million years ago during the Pliocene epoch
(5.3 to 1.6 million years ago). During this time
fundamental changes in morphology and behavior
occurred, presumably to adapt to changing
the habitat from the forest to the plains:
bipedalism, a dramatic increase of brain
volume, and anatomic changes in the pharynx
to allow speech were accompanied by tool
making and other complex behavior.
The earliest fossils of Homo sapiens are from
100000 years ago. Modern humans as they
exist today date back about 30000–40000
years.
have been found in Eastern Africa. They are attributed
to an extinct genus, Australopithecus.
Several different species originated about 4.5 to
2 million years ago during the Pliocene epoch
(5.3 to 1.6 million years ago). During this time
fundamental changes in morphology and behavior
occurred, presumably to adapt to changing
the habitat from the forest to the plains:
bipedalism, a dramatic increase of brain
volume, and anatomic changes in the pharynx
to allow speech were accompanied by tool
making and other complex behavior.
The earliest fossils of Homo sapiens are from
100000 years ago. Modern humans as they
exist today date back about 30000–40000
years.
Geographic distribution of important hominid find
Two hypotheses for the origin of modern
humans have been put forward. The first is that
evolution was multiregional, that is, early
humans migrated to different geographic regions,
resulting in parallel evolution throughout
the world. The other hypothesis assumes
that all modern humans moved through the
middle east into Europe and Asia between
50000 and 100000 years ago and replaced
humans have been put forward. The first is that
evolution was multiregional, that is, early
humans migrated to different geographic regions,
resulting in parallel evolution throughout
the world. The other hypothesis assumes
that all modern humans moved through the
middle east into Europe and Asia between
50000 and 100000 years ago and replaced
Relationship of modern humans and Neandertals
Modern humans and Neandertals coexisted
about 30000–40000 years ago. Recent studies
indicate that Neandertals did not contribute
mitochondrial DNA to modern humans. At two
different locations about 2000km apart,
mtDNA from Neandertal specimens at Feldhofer
Cave, Neandertal, and Mezmaiskaya Cave
in the northern Caucasus showed only 3.48%
sequence divergence.
about 30000–40000 years ago. Recent studies
indicate that Neandertals did not contribute
mitochondrial DNA to modern humans. At two
different locations about 2000km apart,
mtDNA from Neandertal specimens at Feldhofer
Cave, Neandertal, and Mezmaiskaya Cave
in the northern Caucasus showed only 3.48%
sequence divergence.
Phylogenetic tree reconstruction from mitochondrial DNA
Genetic studies are consistent with the Out of
Africa hypothesis. The strongest evidence came
froman analysis of mitochondrial DNA from147
modern humans of African, Asian, Australian,
New Guinean, and European origin. The
genealogical tree could be traced back to an ancestral
haplotype presumably 200000 years old
(“mitochondrial Eve”).
Africa hypothesis. The strongest evidence came
froman analysis of mitochondrial DNA from147
modern humans of African, Asian, Australian,
New Guinean, and European origin. The
genealogical tree could be traced back to an ancestral
haplotype presumably 200000 years old
(“mitochondrial Eve”).
Genome Analysis by DNA Microarrays
A microarray or DNA chip is an assembly of
oligonucleotides or other DNA probes, e.g.,
cDNA clones, fixed on a fine grid of surfaces. It is
used to analyze the expression states of a series
of genes represented in cDNA prepared from
mRNA (expression screening) or to recognize
sequence variations in genes (screening for
DNA variation). The advantages of using microarrays
are manyfold: simultaneous large-scale
analysis of thousands of genes at a time, automation,
small sample size, and easy handling
given the right equipment. Several manufacturers
offer highly efficient microarrays that
can accomodate 300000 DNA probes on a highdensity
glass slide of small size (e.g.
1.28cm!1.28 cm).
Two basic types of DNA microarrays can be distinguished,
although many variations are being
developed: (i) microarrays of previously prepared
DNA clones or PCR products that are attached
to the surface, arranged in a high-density
gridded array in two-dimensional linear
coordinates; (ii) microarrays of oligonucleotides
synthesized in situ on a suitable surface.
Both types of DNA arrays can be hybridized
to labeled DNA probes in solution.
oligonucleotides or other DNA probes, e.g.,
cDNA clones, fixed on a fine grid of surfaces. It is
used to analyze the expression states of a series
of genes represented in cDNA prepared from
mRNA (expression screening) or to recognize
sequence variations in genes (screening for
DNA variation). The advantages of using microarrays
are manyfold: simultaneous large-scale
analysis of thousands of genes at a time, automation,
small sample size, and easy handling
given the right equipment. Several manufacturers
offer highly efficient microarrays that
can accomodate 300000 DNA probes on a highdensity
glass slide of small size (e.g.
1.28cm!1.28 cm).
Two basic types of DNA microarrays can be distinguished,
although many variations are being
developed: (i) microarrays of previously prepared
DNA clones or PCR products that are attached
to the surface, arranged in a high-density
gridded array in two-dimensional linear
coordinates; (ii) microarrays of oligonucleotides
synthesized in situ on a suitable surface.
Both types of DNA arrays can be hybridized
to labeled DNA probes in solution.
Gene expression profile by cDNA array
This figure shows amicroarray of 1500 different
cDNAs from the human X chromosome. The
cDNAs were obtained from lymphoblastoid
cells of a normal male (XY) and a normal female
(XX). The cDNAs of the male cells were labeled
with the fluorochrome Cy3 (green) and the
cDNAs of the female cellswere labeledwith Cy5
(red). The inactivation of most genes in one of
the two X chromosomes in female cells leads to
a 1:1 ratio of cDNAs from the expressed genes
in the male and the female X chromosomes
(yellowsignal at most sites because red fluorescence
(female) and green fluorescence (male)
signals are superimposed owing to the similar
expression levels in male and female cells). An
exception is the XIST gene, which regulates X inactivation
(see p. 228). It is expressed on the inactive
X chromosome only.
cDNAs from the human X chromosome. The
cDNAs were obtained from lymphoblastoid
cells of a normal male (XY) and a normal female
(XX). The cDNAs of the male cells were labeled
with the fluorochrome Cy3 (green) and the
cDNAs of the female cellswere labeledwith Cy5
(red). The inactivation of most genes in one of
the two X chromosomes in female cells leads to
a 1:1 ratio of cDNAs from the expressed genes
in the male and the female X chromosomes
(yellowsignal at most sites because red fluorescence
(female) and green fluorescence (male)
signals are superimposed owing to the similar
expression levels in male and female cells). An
exception is the XIST gene, which regulates X inactivation
(see p. 228). It is expressed on the inactive
X chromosome only.
Gene expression patterns in human cancer cell lines
Microarrays analyzing the pattern of expression
in cancer cells can be expected to have a great
impact on diagnosis, surveillance of therapy,
and screening for anticancer drugs. Approximately
8000 genes among 60 cell lines derived
from different types of cancer have been studied
by Ross et al. (2000). A consistent relationship
between gene expression patterns and
tissue of origin was detectable.
Panel 1 shows the cell-line dendrogram relating
the patterns of gene expression with respect to
the tissue of origin of the cell lines as derived
from 1161 cDNAs in 64 cell lines. Panel 2 shows
a colored microarray representation of the data
using Cy5-labeled (red) cDNA reverse-transcribed
from mRNA isolated from the cell lines
compared with Cy3-labeled (green) cDNA
derived from reference mRNA. The columns
(1161 genes) and the rows (60 cell lines) showin
red clusters of increased gene expression at
several locations. These observations forecast
the future of analysis of altered gene expression
patterns in tumor cells. (Figure adapted from
Ross, et al. 2000 with kind permission by
the authors and Nature Genetics;
in cancer cells can be expected to have a great
impact on diagnosis, surveillance of therapy,
and screening for anticancer drugs. Approximately
8000 genes among 60 cell lines derived
from different types of cancer have been studied
by Ross et al. (2000). A consistent relationship
between gene expression patterns and
tissue of origin was detectable.
Panel 1 shows the cell-line dendrogram relating
the patterns of gene expression with respect to
the tissue of origin of the cell lines as derived
from 1161 cDNAs in 64 cell lines. Panel 2 shows
a colored microarray representation of the data
using Cy5-labeled (red) cDNA reverse-transcribed
from mRNA isolated from the cell lines
compared with Cy3-labeled (green) cDNA
derived from reference mRNA. The columns
(1161 genes) and the rows (60 cell lines) showin
red clusters of increased gene expression at
several locations. These observations forecast
the future of analysis of altered gene expression
patterns in tumor cells. (Figure adapted from
Ross, et al. 2000 with kind permission by
the authors and Nature Genetics;
Cell-to-Cell Interactions
Intracellular Signal
Transduction Systems
Multicellular organisms depend on communication
between cells to assure growth,
differentiation, specific functions in different
types of cells, and proper response to external
stimuli. Specific cell–cell interactions between
different types of cells have evolved. A common
leitmotif is the specific binding of an extracellular
signaling molecule (ligand) to a specific receptor
of the target cell to trigger a specific
functional response. The vast variety of
molecules involved in the many different types
of cells can be classified into families of related
structure and function (see Lodish et al., 2000;
Alberts et al., 1994). Two areas are selected
here: the main intracellular functions controlling
growth and the receptor tyrosine kinases.
Transduction Systems
Multicellular organisms depend on communication
between cells to assure growth,
differentiation, specific functions in different
types of cells, and proper response to external
stimuli. Specific cell–cell interactions between
different types of cells have evolved. A common
leitmotif is the specific binding of an extracellular
signaling molecule (ligand) to a specific receptor
of the target cell to trigger a specific
functional response. The vast variety of
molecules involved in the many different types
of cells can be classified into families of related
structure and function (see Lodish et al., 2000;
Alberts et al., 1994). Two areas are selected
here: the main intracellular functions controlling
growth and the receptor tyrosine kinases.
Main intracellular functions controlling growth
Growth factors are a large group of different extracellular
molecules that bind with high specificity
to cell surface receptors (1). Their binding
to the receptor (2) activates intracellular signal
transduction proteins (3). This initiates a cascade
of events resulting in activation of other
proteins (often by phosphorylation) that act as
second messengers (4). Hormones of different
types are a heterogeneous class of signaling
molecules (5). They enter the cell either by diffusion
through the plasma membrane or by
binding to a cell surface receptor (6). Some hormones
require an intranuclear receptor (7).
Eventually the signal cascade results in activation
or inactivation of transcription factors (8).
Before transcription and translation ensue, an
elaborate system of DNA damage recognition
and repair systems (9) make sure that cell proliferation
is safe (cell cycle control, 10). In the
event that faults in DNA structure have not been
repaired prior to replication, an important
pathway sacrifices the cell by apoptosis
molecules that bind with high specificity
to cell surface receptors (1). Their binding
to the receptor (2) activates intracellular signal
transduction proteins (3). This initiates a cascade
of events resulting in activation of other
proteins (often by phosphorylation) that act as
second messengers (4). Hormones of different
types are a heterogeneous class of signaling
molecules (5). They enter the cell either by diffusion
through the plasma membrane or by
binding to a cell surface receptor (6). Some hormones
require an intranuclear receptor (7).
Eventually the signal cascade results in activation
or inactivation of transcription factors (8).
Before transcription and translation ensue, an
elaborate system of DNA damage recognition
and repair systems (9) make sure that cell proliferation
is safe (cell cycle control, 10). In the
event that faults in DNA structure have not been
repaired prior to replication, an important
pathway sacrifices the cell by apoptosis
Receptor tyrosine kinase family
Like the G protein-coupled receptors (GPCRs,
see p. 268) and their effectors, the receptor tyrosine
kinases (RTKs) are a major class of cell
surface receptors. Their ligands are soluble or
membrane-bound growth factor proteins. RTK
signaling pathways involve a wide variety of
other functions. Mutations in RTKs may send a
proliferative signal even in the absence of a
growth factor, resulting in errors in embryonic
development and differentation (congenital
malformation) or cancer.
see p. 268) and their effectors, the receptor tyrosine
kinases (RTKs) are a major class of cell
surface receptors. Their ligands are soluble or
membrane-bound growth factor proteins. RTK
signaling pathways involve a wide variety of
other functions. Mutations in RTKs may send a
proliferative signal even in the absence of a
growth factor, resulting in errors in embryonic
development and differentation (congenital
malformation) or cancer.
RTK families
Of the more than
twenty different RTK families, five examples are
selected here: the epidermal growth factor receptor
(EGFR); insulin receptor (IR); fibroblast
growth factor receptor (FGFR) types 1, 2, and 3;
platelet-derived growth factor (PDGFR); and
RET (rearranged during transformation).
These receptors share structural features, although
they differ in function. All have a single
transmembrane domain and an intracellular tyrosine
kinase domain of slightly varied size. The
extracellular domains consist of evolutionarily
conserved motifs: cystein-rich regions, immunoglobulin
(Ig)-like domains, fibronectin repeats
in the tyrosine kinase with Ig and the EGF.
RTK mutations cause a group of important
human diseases and malformation syndromes.
The phenotypes of the mutations differ according
to the particular type of RTK involved and
the type of mutation.
twenty different RTK families, five examples are
selected here: the epidermal growth factor receptor
(EGFR); insulin receptor (IR); fibroblast
growth factor receptor (FGFR) types 1, 2, and 3;
platelet-derived growth factor (PDGFR); and
RET (rearranged during transformation).
These receptors share structural features, although
they differ in function. All have a single
transmembrane domain and an intracellular tyrosine
kinase domain of slightly varied size. The
extracellular domains consist of evolutionarily
conserved motifs: cystein-rich regions, immunoglobulin
(Ig)-like domains, fibronectin repeats
in the tyrosine kinase with Ig and the EGF.
RTK mutations cause a group of important
human diseases and malformation syndromes.
The phenotypes of the mutations differ according
to the particular type of RTK involved and
the type of mutation.
Types of Cell Surface Receptors
Specific receptors on cell surfaces (and in the
nucleus or cytosol) convey cell-to-cell signals
into the cells and the functional answers. The
basic structures of their genes are similar because
they have been derived from a relatively
small group of ancestral genes. They way they
bind to the ligand (the signal-releasing
molecule) and the functional answer of the cell
are specific. When a ligand binds to a receptor, a
series of reactions is initiated that alters the
function of the cell. Receptors with direct and
indirect ligand effects can be distinguished.
nucleus or cytosol) convey cell-to-cell signals
into the cells and the functional answers. The
basic structures of their genes are similar because
they have been derived from a relatively
small group of ancestral genes. They way they
bind to the ligand (the signal-releasing
molecule) and the functional answer of the cell
are specific. When a ligand binds to a receptor, a
series of reactions is initiated that alters the
function of the cell. Receptors with direct and
indirect ligand effects can be distinguished.
Cell surface receptors with direct ligand effect
Many hormones cannot pass through the
plasma membrane; instead, they interact with
cell surface receptors. Their effects are direct
and very rapid. With ligand-activated (or ligand-
gated) ion channels (1), binding of the ligand
to the receptor changes the conformation of
the receptor protein. This causes an ion-specific
channel in the receptor protein to open. The resulting
flow of ions changes the electric charge
of the cell membrane. Receptors with ligandactivated
protein kinase (2) further activate a
substrate protein. Most protein kinases
phosphorylate tyrosine (tyrosine kinase),
serine, or threonine by transferring a phosphate
residue from adenosine triphosphate (ATP),
which is then converted to adenosine diphosphate
(ADP). Other receptors mediate the
removal of phosphate from a phosphorylated
tyrosine side chain by means of their
phosphatase activity (3). With one important
type of receptor, ligand binding activates
guanylate cyclase (4), which catalyzes the formation
of cyclic guanosine monophosphate
(cGMP) from guanosine triphosphate (GTP).
The cGMP functions as a second messenger and
brings about a rapid change of activity of
enzymes or nonenzymatic proteins. Removal or
degradation of the ligand reduces the concentration
of the second messenger and ends the
reaction.
plasma membrane; instead, they interact with
cell surface receptors. Their effects are direct
and very rapid. With ligand-activated (or ligand-
gated) ion channels (1), binding of the ligand
to the receptor changes the conformation of
the receptor protein. This causes an ion-specific
channel in the receptor protein to open. The resulting
flow of ions changes the electric charge
of the cell membrane. Receptors with ligandactivated
protein kinase (2) further activate a
substrate protein. Most protein kinases
phosphorylate tyrosine (tyrosine kinase),
serine, or threonine by transferring a phosphate
residue from adenosine triphosphate (ATP),
which is then converted to adenosine diphosphate
(ADP). Other receptors mediate the
removal of phosphate from a phosphorylated
tyrosine side chain by means of their
phosphatase activity (3). With one important
type of receptor, ligand binding activates
guanylate cyclase (4), which catalyzes the formation
of cyclic guanosine monophosphate
(cGMP) from guanosine triphosphate (GTP).
The cGMP functions as a second messenger and
brings about a rapid change of activity of
enzymes or nonenzymatic proteins. Removal or
degradation of the ligand reduces the concentration
of the second messenger and ends the
reaction.
Hormones with immediate effects on cells
Important examples of hormones that function
as ligands are amino acid derivates, arachidonic
acid derivatives, and many peptide hormones.
as ligands are amino acid derivates, arachidonic
acid derivatives, and many peptide hormones.
...........
Epinephrine, norepinephrine, and histamine
act directly and very rapidly. Peptide hormones
such as insulin or adrenocorticotropic hormone
(ACTH) initially occur as precursor polypeptides,
which are split by specific proteases to
form active molecules. Some peptide hormones
are coded for by a common gene; differential
RNA splicing of the transcript of this gene produces
different precursors for translation.
(Abbreviations used: ACTH, adrenocorticotropic
hormone; FSH, follicle-stimulating
hormone; LH, leutinizing hormone; TSH, thyroid-
stimulating hormone.) (Figure data after
Lodish et al., 2000.)
act directly and very rapidly. Peptide hormones
such as insulin or adrenocorticotropic hormone
(ACTH) initially occur as precursor polypeptides,
which are split by specific proteases to
form active molecules. Some peptide hormones
are coded for by a common gene; differential
RNA splicing of the transcript of this gene produces
different precursors for translation.
(Abbreviations used: ACTH, adrenocorticotropic
hormone; FSH, follicle-stimulating
hormone; LH, leutinizing hormone; TSH, thyroid-
stimulating hormone.) (Figure data after
Lodish et al., 2000.)
Cell surface receptors with indirect ligand effect
Many cell surface receptors act indirectly. When
they bind to a ligand they induce a series of intracellular
activation steps. This reaction system
consists of a receptor protein, a protein (G
protein) bound to a guanosine residue, and an
enzyme to be activated. Ligand binding alters
the receptor protein and activates the G protein
(2). This moves to the effector, e.g., an enzyme
complex (3), and activates it (4). In this way, a
second messenger is formed that triggers
further reactions in the cell, e.g., cyclic adenosine
monophosphate (cAMP) bymeans of the
enzyme adenylate cyclase
they bind to a ligand they induce a series of intracellular
activation steps. This reaction system
consists of a receptor protein, a protein (G
protein) bound to a guanosine residue, and an
enzyme to be activated. Ligand binding alters
the receptor protein and activates the G protein
(2). This moves to the effector, e.g., an enzyme
complex (3), and activates it (4). In this way, a
second messenger is formed that triggers
further reactions in the cell, e.g., cyclic adenosine
monophosphate (cAMP) bymeans of the
enzyme adenylate cyclase
G Protein-coupled Receptors
The indirect transmission of signals into the cell
is mediated by transmembrane proteins, which
traverse the cell membrane. A first messenger,
e.g., a hormone like epinephrine, triggers an intracellular
reaction by binding to a specific receptor.
This leads to activation of a second messenger,
which in turn initiates a series of reactions
that result in a change of cell function.
Many of the genes for the different proteins involved
in the indirect transmission of signals
are known.
is mediated by transmembrane proteins, which
traverse the cell membrane. A first messenger,
e.g., a hormone like epinephrine, triggers an intracellular
reaction by binding to a specific receptor.
This leads to activation of a second messenger,
which in turn initiates a series of reactions
that result in a change of cell function.
Many of the genes for the different proteins involved
in the indirect transmission of signals
are known.
Stimulatory G protein (Gs) and hormone–receptor complex
There are many endogenous messengers (hormones)
with their own specific receptors. First
the hormone binds to the receptor (formation
of a hormone–receptor complex). The intracellular
transmission of signals is mainly carried
out by special guanine-nucleotide-binding
proteins, or G proteins. By binding to guanosine
triphosphate (GTP, a nucleotide composed of
guanine, a sugar, and three phosphate groups),
the G protein becomes activated and initiates
further reactions. G proteins consist of three
subunits: !, ", and #. The ! subunit (stimulatory
G protein, Gs) binds to the effector protein. Immediately
thereafter, G! is inactivated (GTPase)
by hydrolysis of GTP to GDP (guanosine diphosphate).
This transforms the G protein back
into an inactive form (Gi).
with their own specific receptors. First
the hormone binds to the receptor (formation
of a hormone–receptor complex). The intracellular
transmission of signals is mainly carried
out by special guanine-nucleotide-binding
proteins, or G proteins. By binding to guanosine
triphosphate (GTP, a nucleotide composed of
guanine, a sugar, and three phosphate groups),
the G protein becomes activated and initiates
further reactions. G proteins consist of three
subunits: !, ", and #. The ! subunit (stimulatory
G protein, Gs) binds to the effector protein. Immediately
thereafter, G! is inactivated (GTPase)
by hydrolysis of GTP to GDP (guanosine diphosphate).
This transforms the G protein back
into an inactive form (Gi).
Four hormone classes
Four principal classes of hormones can be
differentiated: (1) amino acid derivatives such
as epinephrine and epinephrine derivatives; (2)
polypeptides such as glucagon; (3) steroids
such as cortisol and its derivatives; and (4) fatty
acid derivatives such as the prostaglandins.
differentiated: (1) amino acid derivatives such
as epinephrine and epinephrine derivatives; (2)
polypeptides such as glucagon; (3) steroids
such as cortisol and its derivatives; and (4) fatty
acid derivatives such as the prostaglandins.
Formation and hydrolysis of cAMP
The key reaction is the formation of cyclic adenosine
monophosphate (cAMP) fromadenosine
triphosphate (ATP) by means of adenylate cyclase.
Intracellular cyclic AMP transmits the activation
initiated by the hormone–receptor
complex without a molecule having passed
through the plasma membrane. cAMP is responsible
for many physiological reactions. It
becomes inactivated when converted into adenosine
monophosphate (AMP) by phosphodiesterase.
cGMP (cyclic guanosine monophosphate)
functions in the same manner as
cAMP to initiate an intracellular reaction.
monophosphate (cAMP) fromadenosine
triphosphate (ATP) by means of adenylate cyclase.
Intracellular cyclic AMP transmits the activation
initiated by the hormone–receptor
complex without a molecule having passed
through the plasma membrane. cAMP is responsible
for many physiological reactions. It
becomes inactivated when converted into adenosine
monophosphate (AMP) by phosphodiesterase.
cGMP (cyclic guanosine monophosphate)
functions in the same manner as
cAMP to initiate an intracellular reaction.
G protein cycle to activate adenylate cyclase
When a hormone binds to its specific receptor, a
structural change occurs (1). This activates the
! subunit of the G protein, which separates
from the " and # subunits (2). The stimulatory G
protein (Gs-!) binds to the effector protein, usually
adenylate cyclase, and activates it (3). cAMP
is then formed from ATP, while GTP is hydrolyzed
to GDP at the G-! subunit. This inactivates
the effector protein and the formation of cAMP
is terminated. Thus, the signal is of very short
duration, and the initial conditions are rapidly
restored. Several toxins exert their activity by
interrupting this cycle. For example, cholera
toxin inhibits inactivation of the Gs-! protein so
that adenylate cyclase remains activated and
large amounts of sodium and water are lost
through the intestinal mucous membranes.
structural change occurs (1). This activates the
! subunit of the G protein, which separates
from the " and # subunits (2). The stimulatory G
protein (Gs-!) binds to the effector protein, usually
adenylate cyclase, and activates it (3). cAMP
is then formed from ATP, while GTP is hydrolyzed
to GDP at the G-! subunit. This inactivates
the effector protein and the formation of cAMP
is terminated. Thus, the signal is of very short
duration, and the initial conditions are rapidly
restored. Several toxins exert their activity by
interrupting this cycle. For example, cholera
toxin inhibits inactivation of the Gs-! protein so
that adenylate cyclase remains activated and
large amounts of sodium and water are lost
through the intestinal mucous membranes.
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