1. THE HUMEN PERSPECTIVE THE HUMEN PERSPECTIVE Disorders Associated with
G protein-Coupled Receptors(GPCR)
KARP Page 631
王珏 李青连
05年11月
Disorders Associated with
G protein-Coupled Receptors(GPCR)
KARP Page631
王珏 李青连
05年11月

2. What is G protein?
What is GPCR?
Diseases associated with G protein and GPCR!

3. 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

4. Heterotrimeric G-protein 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”
bind to and
hydrolize GTP
Two switch domains have been identified, that change position when GTP substitutes for GDP on Ga.

5. 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 beta-gamma complex.

7. The classification is based on the G subunits and the effectors to which they couple.

8. 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.

10. 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.

11. 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.

12. cAMP signal transduction pathway

15. The importance of GPCR
 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 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 .

16. 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

17. 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 ?

18. 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

19. 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

20. adenoma(腺瘤 )

21. Kaposi’s sarcoma(卡波氏肉瘤)

22. 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.

24. Treatment: Surgery: Radiation Therapy: Chemotherapy:
Biological Therapy:
Hormone Therapy:
Viral vector treatment

25. Viral vector treatment

26. 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 .

27. thank you !!!