Disorders Associated with GPCRs

By 刘芬 1080800103 麦星宇 1080800105

Fig.1 Putative membrane tography of G protein coupled receptors

represents the largest family of genes encoded by the human genome. Their importance in human biology is reflected by the fact that over one-third of all prescription drugs act as ligands that bind to this huge superfamily of receptor.

A number of inherited disorders have been traced to defects in both GPCRs and hetreotrimeric G protein.

Various types of diseases caused by defective GPCRs

A rod photoreceptor cell

Retinitis Pigment (RP)

An inherited disease.

Characteristic :

progessive degeneration of the retina and eventual blindness.

Rhodopsin, a light-sensitive G protein-coupled receptor, is located in the flattened membrane disks of the outer segment.

The rhodopsin of cattle

can be caused by mutations in the gene that encodes rhodopsin.

Two kinds of mutations:

1. lead to premature termination or imporpering of the rhodopsin protein.

2. Lead to the synthesis of a rhodopsin molecule.

Thyroid tumor

thyroid cartilage

Thyroid side leaves

thyroidtrachea

Normal thyroid cells that secrete thyroid hormone only in response to stimulation by the pituitary hormone TSH.

But once the mutation, adenoma secrete large quantities of thyroid hormone without having to be stimulated by TSH.

The third intracellular loop

mutation

activates a G protein on its inner surface

Consititutively

signal through the pathway

Thyroid hormone secretion

Excessive cell prolifercation

tumor

Continual

The arrow is point to the swell

Pic. Take from different state

G protein is composed of αsubunit ， βs

ubunit and r subunit. Mutation in

genes that encode the subunits of het-

erotrimeric G protein can also lead to in-

herited disorders. The inherited disorders

is known as G protein diseases.

疾病 缺陷 G蛋白

Albright’s hereditary osteodystrophy and pseudohypoparathyroidisms

奥尔布赖特的遗传性骨病和假性甲状旁腺功能减退症

Gsa

McCune-Albright syndrome 麦克卡尼 - Albright 综合征 Gsa

Pituitary,thyroid tumors (gsp oncogene) 垂体，甲状腺肿瘤（ gsp 癌基因） Gia

Adrenocortical,ovarian tumors (gsp oncogene)

肾上腺皮质，卵巢肿瘤（ gsp 癌基因）

Gsa

Combined precocious puberty and pseudohypoparathyroidism

性早熟与假性甲状旁腺功能减退综合症

Gsa

precocious puberty and hypoparathyroidism 性早熟与甲状旁腺功能减退综合症 Gsa

Three types:

G protein remained in the active state; G protein remained in the inactive state;

G protein remained in the active –inactive state.

The alteraction in amino acid sequence

The mutant of G protein

Mutation in genes

In the presence and absence of bound ligand,There are two effects ：

One is :

At temperatures below normal body temperature, G protein remains active.

The other is :

At normal temperatures, G protein remains inactive.

Normally,the endocrine cells of the testes initiate testosterone production at the time of puberty in response to the pituitary hormone LH. The testicular cells of the patients bearing the G protein mutation were stimulated to synthesize cAMP in the absence of the LH ligand, leading to premature synthesis of testosterone and precocious puberty.

The testes,which are housed outside of body’s core ,have a lower temperature than the body’s visceral organs (33 vs.37 ) .℃ ℃

The mutation in this same G protein

in the cells of the parathyroid glands, which

funcation at a temperature of 37 ,caused℃the G protein to remain inactive. The cells

of the parathyoid glands could not respond

to stimuli that would normally cause them to

secrete parathyroid hormone,leading to the

condition of Hypoparathyroidism.

Certain alleles of the gene encoding the β2 adrenergic receptor

an increased likeli-hood of developing asthma or high blood pressure.

Certain alleles of a dopamine receptor

Increased risk of substance abuse or schizophrenia

Certain alleles of a chemokine receptor

Prolonged survival in HIV-infected individual

Identify associations between disease

susceptibility and genetic polymorphisms

is a current focus of clinical research.