Download PPT

THE HUMEN
PERSPECTIVE
——Disorders Associated with
G protein-Coupled Receptors
Karp
P631
焦义（1030801261）
2005年12月
The human genome may encode as many as 2000
different GPCRs. Their importance in human
biology is reflected by the fact that more than
one-quarter 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 .
人类基因组能够编码多达2000中不同的G蛋
白偶联受体（GPCRs）。大约有1/4的处方药品
是作为与这类受体超家族中的某一受体的配基
而发挥作用的，由此可以看出G蛋白受体的重
要性。
相当一部分遗传性紊乱都可以上溯到GPCRs
和异三聚G蛋白的缺陷。

What is G protein?

What is GPCR?

Signal transduction.

Diseases associated with G
protein and GPCR.
1、Discovery
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
Alfred G. Gilman
Martin Rodbell
University of Texas
Southwestern Medical
Center at Dallas Dallas,
TX, USA born 1941
National Institute of
Environmental Health
Sciences Research
Triangle Park, NC,
USA
Born 1925, died 1998
2 、Structure
“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
G a.
2、Structure
三聚体GTP结合调节蛋白，简称G蛋白，位于质
膜内胞浆一侧，由α βγ三个亚基构成。Βγ二聚
体通过共价结合锚于膜上起稳定α亚基的作用，而α
亚基本身具有GTP酶活性，能催化所结合的ATP水
解，恢复无活性的三聚体状态。G蛋白在信号转导过
程中起着分子开关的作用。当α亚基与GDP结合时
处于关闭状态，与GTP结合时处与开启状态。
back
1.structure
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.
1.structure
右图为G蛋白耦联型
受体该受体为7次跨
膜蛋白，胞外结构域
识别胞外信号分子并
与之结合，胞内结构
域与G蛋白耦联。通
过与G蛋白耦联，调
节相关酶活性，在细
胞内产生第二信使，
从而将胞外信号跨膜
传递到胞内。
图示的八个位点为突
变位置，这些突变会
导致一系列的不正常
现象。
back
Signal transduction
1. 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.
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 animal,and GPCR have many activating pathway.
2.cAMP signal transduction pathway
G-protein coupled receptors (GPCRs) are one of
the largest gene families of signaling proteins.
Residing in the plasma membrane with seven
transmembrane domains, GPCRs respond to
extracellular stimuli that include catecholamine
neurotransmitters, neuropeptides, larger protein
hormones, lipids, nucleotides and other biological
molecules. When a GPCR binds its extracellular
ligand, it interacts with a G-protein to transduce a
signal across the membrane into the cellular
interior.
G-proteins are a heterotrimeric complex
containing a Ga subunit with GTPase activity, as
well as b and g subunits. Ga can exist in an active
state and an inactive state.
Ga in the off state has GDP bound and does not
activate downstream signaling molecules. When a
GPCR is activated by ligand, it stimulates Ga
subunits to bind GTP instead of GDP and become
active, dissociating from the receptor and from
the b/g subunits to activate downstream signaling
factors like the enzyme adenylyl cyclase that
synthesizes cyclic-AMP (cAMP) from ATP. Ga
turns itself back off again with its intrinsic
GTPase activity, hydrolyzing GTP to GDP to
back
become inactive again.
Human Diseases Linked to the G Protein Pathway
Diseases
Albright’s hereditary
osteodystrophy and
pseudohypoparathyroidisms
McCune-Albright syndrome
Pituitary,thyroid tumors
Adrenocortical,ovarian
tumors
Combined precocious
puberty and
peudohypoparathyroidism
Defective G Protein
Gsα
Gsα
Gsα
Giα
Gsα
Thanks!