disorders associated with gpcrs by 刘芬 1080800103 麦星宇 1080800105

of 22/22
Disorders Associated wi th GPCRs By 刘刘 1080800103 刘刘刘 10808001 05

Post on 21-Jan-2016

310 views

Category:

Documents

0 download

Embed Size (px)

TRANSCRIPT

  • Disorders Associated with GPCRsBy 1080800103 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 cellRetinitis 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 cattlecan be caused by mutations in the gene that encodes rhodopsin.

    Two kinds of mutations:lead to premature termination or imporpering of the rhodopsin protein.2. Lead to the synthesis of a rhodopsin molecule.

  • Thyroid tumorthyroid cartilage Thyroid side leavesthyroidtrachea 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

  • mutationactivates a G protein on its inner surfaceConsititutivelysignal through the pathwayThyroid hormone secretionExcessive cell prolifercation tumorContinual

  • The arrow is point to the swellPic. Take from different state

  • G protein is composed of subunitsubunit 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.

  • GAlbrights hereditary osteodystrophy and pseudohypoparathyroidismsGsaMcCune-Albright syndrome- AlbrightGsaPituitary,thyroid tumors (gsp oncogene)gspGiaAdrenocortical,ovarian tumors (gsp oncogene)gspGsaCombined precocious puberty and pseudohypoparathyroidismGsaprecocious puberty and hypoparathyroidismGsa

  • 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 sequenceThe mutant of G protein Mutation in genesIn 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 bodys core ,have a lower temperature than the bodys visceral organs (33vs.37 ) .

  • The mutation in this same G protein in the cells of the parathyroid glands, whichfuncation at a temperature of 37 ,causedthe 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 thecondition of Hypoparathyroidism.

  • Certain alleles of the gene encoding the 2 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 schizophreniaCertain 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.