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THE
PERSPECTIVE
THE HUMEN
HUMEN PERSPECTIVE
Disorders Associated with
Associated
with
G Disorders
protein-Coupled
Receptors(GPCR)
G protein-Coupled Receptors(GPCR)
KARP Page 631
王珏 李青连
KARP Page631
王珏 李青连
05年11月
05年11月

What is G protein?

What is GPCR?
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Diseases associated with G protein
and GPCR!
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Heterotrimeric G-proteins were
discovered and characterized by
Martine Rodbell and his colleagues at
the National Institutes in the early
1970s.
These proteins are referred to as G
proteins because they bind guanine
nucleotides,either GDP or GTP
Heterotrimeric G-protein structure
bind to and
hydrolize GTP
“大G”：由αβγ
三个亚基组成
Gα能与
GTP或GDP结
合，有内在的
GTP酶活性，
起“分子开关
作用”
Two switch
domains have
been
identified,
that change
position when
GTP
substitutes
for GDP on Ga.
The alpha subunit is responsible for GTP and GDP
binding and for GTP hydrolysis, whereas the beta and
gamma subunits are associated in a tightly linked betagamma complex.
PDB 1GP2
PDB 1GP2
G – face view of -propeller
G - side view of -propeller
The
classification is
based on the G
subunits and the
effectors to
which they
couple.
The G-protein coupled
receptor (GPCR) family
transduces
extracellular signals
across the plasma
membrane
They consist of seven
transmembrane helices
that are connected by
loops. The N-terminal
extremity is always
located on the
extracellular side while
the C-terminus
extends into the
cytoplasm.
Signal transduction by GPCR
When a hormone or neurotransmitter binds to a
GPCR, it induces a change in conformation in
the extracellular ligand-binding site. This change
in conformation is transferred across the plasma
membrane and causes a change in the
cytoplasmic loops of the receptor which, in
turn ,leads to an increase in the affinity of the
receptor for a G protein ,they forms a receptor-G
protein complex.
Then interaction with the
receptor induces a
conformational change in
the alpha subunit ,causing
the release of GDP, which
is followed by binding of
GTP.
While in the activated state,
a single receptor can
activate a number of G
protein molecules,
providing a means of signal
amplification.
cAMP signal
transduction
pathway
The importance of GPCR
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GPCRs are activated by a wide variety of
ligands, including neurotransmitters,
hormones, growth factors, odorant molecules
and light, and are encoded by the largest gene
family in most animals .
The human genome may encode as many as
2000 different GPCRs.
Their importance in human biology is
reflected by the fact that more than onequarter of all prescription drugs act as
ligands that bind to this huge superfamily of
receptors.
A number of inherited disorders have been
traced to defects in both GPCRs and
heterotrimeric G protein .
Disorders associated with G protein-coupled
receptors
1. mutation that leads to a loss of function of
the encoded receptor
2.mutations that leads to a “gain of
function”---excessive cell proliferation that
cause the tumor
Disorder associated with G protein
1.precocious puberty:：青春期早熟
2. hypoparathyroidism. 低甲状旁腺激素症
Retinitis pigmentosa(RP)---- 视网膜色素变性
 The property of the disease (疾病的属性)：
an inherited disease
 The main characters of this disease(疾病特征:
progressive degeneration of the retina（视网
膜）and eventual blindness
why does this disorder occur?
what is the answer ?

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This is because :
RP can be caused by mutations in the gene
that encodes rhodopsin (视紫红质),the visual
pigment of the rods（视网膜杆）. Many of
these mutations lead to premature
termination or improper folding of the
rhodopsin（视紫红质 ）protein and its
elimination from the cell before it reaches the
plasma membrane.
Therapy: nowadays there is no therapy
adenoma(腺瘤 ) 和 Kaposi’s sarcoma(卡波
氏肉瘤)
 The property of the diseases(疾病的属性):
was not an inherited disease and was not
gene mutation（基因突变） but was
Somatic mutation（细胞体的突变 ）

The main characters of this disease(疾病特
征):the growth of the cell is not in the
contral and the excessive cell proliferation
adenoma(腺瘤 )
Kaposi’s sarcoma(卡波氏肉瘤)
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The mutation that causes thyroid adenomas is
not found in the normal portion of a patient’s
thyroid but only in the tumor tissue, indicating
that the mutation was not inherited but arose in
one of the cells of the thyroid, which then
proliferated to give rise to the tumor. A
mutation in the cell of the body, such as a
thyroid cell, is called a somatic mutation(细胞体
的突变) to distinguish it from an inherited
mutation(遗传突变) that would be present in all
of the individual’s cell.
somatic mutation is a primary cause of human
cancer.
Treatment:
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Surgery:
Radiation Therapy:
Chemotherapy:
Biological Therapy:
Hormone Therapy:
Viral vector treatment
Viral vector treatment
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The characters of G protein
mutation :
At temperatures below normal body
temperatures , the mutant G protein remained
in the active state, even in the absence of a
bound ligand.In contrast, at normal body
temperatures, the mutant G protein was
inactive ,both in the presence and absence of
bound ligand .