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.
