THE HUMEN THE HUMEN PERSPECTIVEPERSPECTIVE

Disorders Associated with Disorders Associated with G protein-Coupled Receptors(GPCR)G protein-Coupled Receptors(GPCR)

KARP Page 631KARP Page 631王珏 李青连王珏 李青连

0505 年年 1111 月月

THE HUMEN PERSPECTIVETHE HUMEN PERSPECTIVE

Disorders Associated with Disorders Associated with G protein-Coupled Receptors(GPCR)G protein-Coupled Receptors(GPCR)

KARP Page631

王珏 李青连

05 年 11 月

What is G protein?What is G protein?

What is GPCR?What is GPCR?

Diseases associated with G protein aDiseases associated with G protein and GPCRnd GPCR!!

Heterotrimeric G-proteins were discoverHeterotrimeric G-proteins were discovered and characterized by Martine Rodbeled and characterized by Martine Rodbell and his colleagues at the National Institl and his colleagues at the National Institutes in the early 1970s.utes in the early 1970s.

These proteins are referred to as G proteThese proteins are referred to as G proteins because ins because they bind guanine nucleotidthey bind guanine nucleotides,either GDP or GTPes,either GDP or GTP

Heterotrimeric G-protein structurHeterotrimeric G-protein structuree

bind to and bind to and hydrolize GTPhydrolize 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 beta-gamma complex.

G - side view of -propeller

PDB 1GP2

G – face view of -propeller

PDB 1GP2

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 Signal transduction by GPCRGPCR

When a hormone or neurotransmitter binds to a When a hormone or neurotransmitter binds to a GPCR, it induces a change in conformation in tGPCR, it induces a change in conformation in the extracellular ligand-binding site. This changhe extracellular ligand-binding site. This change in conformation is transferred across the plae in conformation is transferred across the plasma membrane and causes a change in the cytsma membrane and causes a change in the cytoplasmic loops of the receptor which, in turn ,loplasmic loops of the receptor which, in turn ,leads to an increase in the affinity of the recepteads to an increase in the affinity of the receptor for a G protein ,they forms a receptor-G protor for a G protein ,they forms a receptor-G protein complex. ein 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 GPCRThe importance of GPCR GPCRsGPCRs are activated by a wide variety of liganare activated by a wide variety of ligan

ds, including neurotransmitters, hormones, grds, including neurotransmitters, hormones, growth factors, odorant molecules and light, anowth factors, odorant molecules and light, and are encoded by the largest gene family in mod are encoded by the largest gene family in most animalsst animals . .

The human genome may encode as many as 2The human genome may encode as many as 2000 different GPCRs.000 different GPCRs.

Their importance in human biology is reflecteTheir importance in human biology is reflected by the fact that more than one-quarter of all d by the fact that more than one-quarter of all prescription drugs act as ligands that bind to tprescription drugs act as ligands that bind to this huge superfamily of receptors. his huge superfamily of receptors.

A number of inherited disorders have been traA number of inherited disorders have been traced to defects in both GPCRs and heterotrimerced to defects in both GPCRs and heterotrimeric G protein .ic G protein .

Disorders associated with G protein-coupled Disorders associated with G protein-coupled receptorsreceptors

11. . mutation that leads to a loss of function omutation that leads to a loss of function of the encoded receptor f the encoded receptor

2.2.mutations that leads to a “gain of functiomutations that leads to a “gain of function”---excessive cell proliferation that causn”---excessive cell proliferation that cause the tumor e the tumor

Disorder associated with G protein Disorder associated with G protein 1.precocious puberty:1.precocious puberty: ：青春期早熟：青春期早熟 2. hypoparathyroidism. 2. hypoparathyroidism. 低甲状旁腺激素症低甲状旁腺激素症

Retinitis pigmentosa(RP)---- Retinitis pigmentosa(RP)---- 视网膜色素变性视网膜色素变性 The property of the disease (The property of the disease ( 疾病的属性疾病的属性 )) ：： an inherited diseasean inherited disease The main characters of this disease(The main characters of this disease( 疾病特疾病特

征征 : progressive degeneration of the retina: progressive degeneration of the retina（视网膜）（视网膜） and eventual blindnessand eventual blindness

why does this disorder occur?why does this disorder occur? what is the answer ?what is the answer ?

This is because :This is because : RP can be caused by mutations in the gene tRP can be caused by mutations in the gene t

hat encodes rhodopsin (hat encodes rhodopsin ( 视紫红质视紫红质 ),the visu),the visual pigment of the rodsal pigment of the rods （视网膜杆）（视网膜杆） . Many o. Many of these mutations lead to premature terminf these mutations lead to premature termination or improper folding of the rhodopsination or improper folding of the rhodopsin（视紫红质 ）（视紫红质 ） protein and its elimination froprotein and its elimination from the cell before it reaches the plasma mem the cell before it reaches the plasma membrane. mbrane.

Therapy: Therapy: nowadays there is no therapynowadays there is no therapy

adenoma(adenoma( 腺瘤 腺瘤 ) ) 和 和 Kaposi’s sarcomaKaposi’s sarcoma(( 卡波氏肉瘤卡波氏肉瘤 ))

The property of the diseases(The property of the diseases( 疾病的属性疾病的属性 ):): was not an inherited disease and was n was not an inherited disease and was not gene mutationot gene mutation （基因突变） （基因突变） but was but was Somatic mutationSomatic mutation （细胞体的突变 ）（细胞体的突变 ）

The main characters of this disease(The main characters of this disease( 疾病疾病特征特征 ):the growth of the cell is not in the c):the growth of the cell is not in the contral and the excessive cell proliferatioontral and the excessive cell proliferationn

adenoma( 腺瘤 )

Kaposi’s sarcoma( 卡波氏肉瘤 )

The mutation that causes thyroid adenomas is The mutation that causes thyroid adenomas is not found in the normal portion of a patient’s tnot found in the normal portion of a patient’s thyroid but only in the tumor tissue, indicating thhyroid but only in the tumor tissue, indicating that the mutation was not inherited but arose in oat the mutation was not inherited but arose in one of the cells of the thyroid, which then proliferne of the cells of the thyroid, which then proliferated to give rise to the tumor. A mutation in the ated to give rise to the tumor. A mutation in the cell of the body, such as a thyroid cell, is called a cell of the body, such as a thyroid cell, is called a somatic mutation(somatic mutation( 细胞体的突变细胞体的突变 )) to distinguish i to distinguish it from an t from an inherited mutation(inherited mutation( 遗传突变遗传突变 )) that wo that would be present in all of the individual’s cell. uld be present in all of the individual’s cell.

somatic mutation is a primary cause of human somatic mutation is a primary cause of human cancer. cancer.

Treatment:Treatment: Surgery:Surgery: Radiation Therapy:Radiation Therapy: Chemotherapy:Chemotherapy: Biological Therapy:Biological Therapy: Hormone Therapy:Hormone Therapy: Viral vector treatmentViral vector treatment

Viral vector treatmentViral vector treatment

The characters of G protein mutatioThe characters of G protein mutation :n :

At temperatures below normal body temperatuAt temperatures below normal body temperatures , the mutant G protein remained in the actires , the mutant G protein remained in the active state, even in the absence of a bound ligand.ve state, even in the absence of a bound ligand.In contrast, at normal body temperatures, the In contrast, at normal body temperatures, the mutant G protein was inactive ,both in the presmutant G protein was inactive ,both in the presence and absence of bound ligand .ence and absence of bound ligand .