THE HUMEN PERSPECTIVE

Disorders Associated with G protein-Coupled Receptors

GPCRs are important in human biology !

• The human genome may encode as many as 2000 different GPCRs.

• More than one-third 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 G protein.

GPCRs Structure

GPCRs 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.

Disorders Associated with GPCRs

• 图示八个位点为突变位置

• Mutations at sites 1,2,5,6,7 and 8 result in constitutive stimulation of the effector.

• Mutations at sites 3 and 4 result in blockage of the receptor’s ability to stimulate the effector.

Disorders Associated with GPCRs

• Mutations that lead to a loss of function of the encoded receptor

retinitis pigmentosa (RP) 视网膜炎• Mutations that lead to a gain of functi

on adenoma (thyroid tumor ) 甲状腺瘤

retinitis pigmentosa (视网膜炎 )

The property of the disease: an inherited disease progressive degeneration of the retina

（视网膜） and eventual blindness

The course of the disease: mutations in the gene that encodes rho

dopsin ( 视紫红质 , 为视杆细胞中的光受体 )

retinitis pigmentosa (视网膜炎 )

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.

Other mutations may lead to the synthesis of a rhodopsin （视紫红质 ） molecule that cannot active its G protein.

retinitis pigmentosa (视网膜炎 )

Mutations at site 8 are found in rhodopsin, the light-sensitive pigment of the retina （视网膜） .

thyroid adenoma （甲状腺瘤）

• Mutations that lead to a gain of function.

• mutations have been found to cause a type of benign thyroid tumor, called an adenoma.

thyroid adenoma （甲状腺瘤）

• Unlike normal thyroid cells that secrete thyroid hormone only in response to stimulation by the pituitary( 垂体的 ) hormone TSH （促甲状腺激素） , the cell of these thyroid adenomas secrete large quantities of thyroid hormone without having to be stimulated by TSH (the receptor is said to act constitutively).

How Does This Happen?

The TSH receptor in these cells contains an amino acid substitution that affects the structure of the third intracellular loop of the protein (mutations at sites 5 or 6).

thyroid adenoma （甲状腺瘤）

　 As a result of the mutation, the TSH receptor constitutively activates a G protein on its inner surface, sending a continual signal through the pathway that leads not only to excessive thyroid hormone secretion but to the excessive cell proliferation that causes the tumor.

This conclusion was verified by introducing the mutant gene into cultured cells that normally lack this receptor and demonstrating that the synthesis of the mutant protein and its incorporation into the plasma membrane led to the continuous production of cAMP in the genetically engineered cells.

Adenoma is not an inherited disease !

• A mutation in a cell of the body is called a somatic mutation to distinguish it from an inherited mutation that would be present in all of the individual’s cells.

• 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.

• somatic mutations are a primary cause of human cancer.

• At least one cancer-causing virus has been shown to encode a protein that acts as a constitutively active GPCR.

• The virus is a type of herpes virus that is responsible for kaposi’s sarcoma( 卡波氏肉瘤 ).

• The virus genome encodes a constitutively active receptor for interleukin-8, which stimulates signaling pathways that control cell proliferation