Transcript THE HUMEN PERSPECTIVE

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
function
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
rhodopsin (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