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G-Protein Coupled Receptors (GPCRs)
Disampaikan kembali oleh:
Yance Anas, M.Sc., Apt.
Bag. Farmakologi & Toksikologi
Fakultas Farmasi Universitas Wahid Hasyim Semarang
G-Protein Coupled Receptors (GPCRs)
Also Knows:
• G Protein-linked receptors
• G Protein-link to 2nd Massangers
• Seven-Transmembrane Receptors (7-TMR)
• “G Protein”
Guanine nucleotide-binding proteins
Guanosine triphospate = GTP
Guanosine diphospate = GDP
G-Protein Coupled Receptors (GPCRs)
G-Protein Coupled Receptors (GPCRs)
•
•
•
•
Very important physiologically
Very diverse in function
Only found in eukaryotes
The target of about 40% of all
drugs
• Two main signal transduction
pathway
– cAMP-dependent pathway
– IP3/DAG pathway
Nature Reviews Molecular Cell Biology 3, 639-650 (2002)
SEVEN-TRANSMEMBRANE RECEPTORS
•
•
Kristen L. Pierce, Richard T. Premont & Robert J. Lefkowitz
The Howard Hughes Medical Institute and the Departments of Medicine and
Biochemistry, Box 3821, Duke University Medical Center, Durham, North Carolina,
27710, USA.
• Disebut sebagai Seventransmembrane receptors
• Merupakan jenis reseptor
transmembran terbanyak (dalam
tubuh)
• Terdapat pada semua jaringan tubuh
• Merupakan target aksi sebagian besar
obat-obatan.
SEVEN-TRANSMEMBRANE RECEPTORS
Extracellular
NH2
loops
N -Terminal chain
Membrane
VII
VI
V
IV
III
II
I
Transmembrane
helix
G-Protein
binding region
HO2C
C -Terminal chain
Variable
intracellular loop
Struktur Dasar
• 7 Transmembrane Domains (TMDs),
• 3 intracellular loops,
• 3 extracellular loops,
• N- and C-teminals
Intracellular loops
Pharmacol Ther. 2004 Jul;103(1):21-80
Basic structure: GPCRs are lipoproteins
Diversity of GPRS Receptors
The EMBO Journal (1999) 18, 1723–1729
large variety of different agonists
Diversity of physiological responses to GPCR stimulation
TARGET TISSUE
HORMONE
MAJOR RESPONSE
Thyroid gland
thyroid-stimulating hormone
(TSH)
thyroid hormone synthesis and
secretion
Adrenal cortex
adrenocorticotrophic hormone
(ACTH)
cortisol secretion
Ovary
luteinizing hormone (LH)
progesterone secretion
Muscle
adrenaline
glycogen breakdown
Bone
parathormone
bone resorption
Heart
adrenaline
increase in heart rate and force
of contraction
Liver
glucagon
glycogen breakdown
Kidney
vasopressin
water resorption
Fat
adrenaline, ACTH, glucagon,
TSH
triglyceride breakdown
TARGET TISSUE
SIGNALING MOLECULE
MAJOR RESPONSE
Liver
vasopressin
glycogen breakdown
Pancreas
acetylcholine
amylase secretion
Smooth muscle
acetylcholine
contraction
Blood platelets
thrombin
aggregation
Receptor activation of heterotrimeric G-proteins.
Basic model
Hollinger et al. 2000 Pharmacological Reviews
What are “G Proteins”?
• Heterotrimeric GTP-binding proteins, terdiri dari 3
subunit:
• Subunit α
• Subunit β
• Subunit γ
What are G Protein-linked 2nd massangers
• Target selular (protein/enzim) dengan fungsi tertentu (mis: membuat
produk) ketika berinteraksi dengan “protein G”
What are G Protein-linked 2nd massangers
Two important Signal Pathway
Two important Signal Pathway
Two important
Signal Pathway
Two important Signal Pathway
Two important Signal Pathway
Two important Signal Pathway
Two important Signal Pathway
C-AMP dependent pathway
• Gi
M2, α2, D2
• Gs
Β1, β2, D1, H2, V2
IP3/DAG Pathway
• Gq
H1, α3, V1, M1, M3
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