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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