Angiotensin Type 1 Receptor and β-arrestin. Ki-Seok Kim, M.D. Jeju National University Hospital
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1 Angiotensin Type 1 Receptor and β-arrestin Ki-Seok Kim, M.D. Jeju National University Hospital
2 GPCR in Heart RAS system Angiotensin II and AT1R β-arrestin Biased Agonism of AT1R AT1R β-arrestin biased Agonist Effects on Cardiac Performance Effects on HF model Effects on Ischemia Reperfusion Injury
3 Classification of Receptors Intracellular receptors (for lipid soluble messengers) function in the nucleus as transcription factor to alter the rate of transcription of particular genes Plasma membrane receptors (for lipid insoluble messengers)
4 Types of Cell Membrane Receptor 1. G-Protein Coupled Receptor (GPCR) 2. Ion Channel Receptor 3. Tyrosine Kinase Receptor 4. Receptor with Intrinsic Enzymatic Activity
5 GPCR Classes Class A: Rhodopsin like (most of mammalian GPCR) Class B: Secretin like Class C: Metabotropic glutamate / pheromone Class D: Fungal pheromone Class E: camp receptors Frizzled/Smoothened family Putative families: * Ocular albinism proteins * Insect odorant receptors * Plant Mlo receptors * Nematode chemoreceptors * Vomeronasal receptors (V1R & V3R) * Taste receptors T2R Orphans: * Putative / unclassified GPCRs non-gpcr families: * Class Z: Archaeal/bacterial/fungal opsins
6 * Class A Rhodopsin like o Amine o Peptide o Hormone protein o (Rhod)opsin o Olfactory o Prostanoid o Nucleotide-like o Cannabinoid o Platelet activating factor o Gonadotropin-releasing hormone o Thyrotropin-releasing hormone & Secretagogue o Melatonin o Viral o Lysosphingolipid & LPA (EDG) o Leukotriene B4 receptor o Class A Orphan/other GPCR Classes * Class C Metabotropic glutamate / pheromone o Metabotropic glutamate o Calcium-sensing like o Putative pheromone receptors o GABA-B o Orphan GPRC5 o Orphan GPCR6 o Bride of sevenless proteins (BOSS) o Taste receptors (T1R) * Class D Fungal pheromone o Fungal pheromone A-Factor like (STE2,STE3) o Fungal pheromone B like (BAR,BBR,RCB,PRA) o Fungal pheromone M- and P-Factor * Class E camp receptors * Class B Secretin like o Calcitonin o Corticotropin releasing factor o Gastric inhibitory peptide o Glucagon o Growth hormone-releasing hormone o Parathyroid hormone o PACAP o Secretin o Vasoactive intestinal polypeptide o Diuretic hormone o EMR1 o Latrophilin o Brain-specific angiogenesis inhibitor (BAI) o Methuselah-like proteins (MTH) o Cadherin EGF LAG (CELSR) o Very large G-protein coupled receptor * Frizzled/Smoothened family o frizzled o Smoothened Putative families: * Ocular albinism proteins * Insect odorant receptors * Plant Mlo receptors * Nematode chemoreceptors * Vomeronasal receptors (V1R & V3R) * Taste receptors T2R Orphans: * Putative / unclassified GPCRs non-gpcr families: * Class Z Archaeal/bacterial/fungal opsins
7 Rhodopsin family: amine receptors Acetylcholine (muscarinic) Adrenaline Dopamine Histamine Serotonin Octopamine Rhodopsin family: peptide receptors Angiotensin Apelin Bombesin Bradykinin C5a anaphylatoxin CC Chemokine CXC Chemokine CX3C Chemokine C Chemokine Cholecystokinin Endothelin fmet-leu-phe Galanin Ghrelin KiSS1-derived peptide Melanocortin Motilin Neuromedin U Neuropeptide FF Neuropeptide S Neuropeptide Y Neuropeptide W / neuropeptide B Neurotensin Orexigenic neuropeptide QRFP Opioid Orexin Oxytocin Prokineticin Somatostatin Tachykinin Urotensin II Vasopressin Protease-activated (thrombin) Adrenomedullin (G10D) GPR37 / endothelin B like Chemokine receptor like Melanin-concentrating hormone Follicle stimulating hormone Lutropin-choriogonadotropic hormone Thyrotropin GPCR Ligands Rhodopsin family: other receptors Rhodopsin Olfactory Prostaglandin Prostacyclin Thromboxane Adenosine Purine / pyrimidine Cannabinoid Platelet activating factor Gonadotropin-releasing hormone Thyrotropin-releasing hormone Melatonin Lysosphingolipid and LPA (EDG) Leukotriene B4 receptor SREB Mas proto-oncogene & Mas-related (MRGs) RDC1 EBV-induced Relaxin LGR like Free fatty acid G protein-coupled bile acid Nicotinic acid GPR GPR45 like Cysteinyl leukotriene Putative / unclassified Class A GPCRs Secretin family Calcitonin Corticotropin releasing factor Gastric inhibitory peptide Glucagon Growth hormone-releasing hormone Parathyroid hormone PACAP Secretin Vasoactive intestinal polypeptide EMR1 Latrophilin Brain-specific angiogenesis inhibitor (BAI) Methuselah-like proteins (MTH) Cadherin EGF LAG (CELSR) Putative / unclassified Class B GPCRs Metabotropic glutamate family Glutamate (metabotropic) Extracellular calcium-sensing GABA-B Pheromone (V2R) Taste receptors (T1R) Orphan GPRC5 Orphan GPCR6 Bride of sevenless proteins (BOSS) Putative / unclassified Class C GPCRs Other families Frizzled / Smoothened family Ocular albinism proteins Vomeronasal receptors (V1R) Taste receptors (T2R) Insect odorant receptors Nematode chemoreceptors Plant Mlo receptors Fungal pheromone camp (Dictyostelium) Bacterial rhodopsin
8 GPCR in Heart Adrenergic receptor Cholinergic receptor Adenosine receptor Endothelin receptor Angiotensin receptor Class A: Rhodopsin like Peptide Receptor Cardiomyocyte, Fibroblast, VSMC
9 Why is GPCR important? GPCRs in disease states Disease states associated with GPCR mutations GPCRs are good drug targets 50% of subscription drugs interact with GPCRs Hypertension, Stomach ulcers, Migraine, Allergies
10 GPCRs GPCRs are the largest single target class for drug action Overington et al. Nature Reviews Drug Discovery, 2006
11 GPCR in Heart RAS system Angiotensin II and AT1R β-arrestin Biased Agonism of AT1R AT1R β-arrestin biased Agonist Effects on Cardiac Performance Effects on HF model Effects on Ischemia Reperfusion Injury
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14 GPCR in Heart RAS system Angiotensin II and AT1R β-arrestin Biased Agonism of AT1R AT1R β-arrestin biased Agonist Effects on Cardiac Performance Effects on HF model Effects on Ischemia Reperfusion Injury
15 Angiotensin Type 1 Receptor 7 TMR ; AKA GPCR N-termial ; ligand binding site C-terminal ; GDP binding site
16 Components and Major Actions of the Kallikrein-Kinin and Renin-Angiotensin systems Kininogen Angiotensinogen kallikrein renin Bradykinin (BK) Angiotensin I BKB receptor ACE endopeptides Vasodilation Inactive peptides NO prostaglandins EDHF tpa AT1 receptors AT2 receptors Oxidation Vasocontriction Proliferation Matrix Formation Aldosterone Secretion Vasodilation Antiproliferation Apoptasis AT3 receptors Aldosterone Secretion Ang II AT4 receptors Vascular integrity PAI-1 Ang (1 7) MAS receptor ACE Vasodilation Antiproliferation Inactive Peptides
17 Angiotensin II & AT1R Angiotensinogen ACE renin Angiotensin I - Octapeptide hormone - most potent presser substance known (direct arter iolar vasoconstriction) - increases sympathetic vasomotor discharge - decreases renin release (negative feedback) Ang II AT1R AT2R
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19 GPCR in Heart RAS system Angiotensin II and AT1R β-arrestin Biased Agonism of AT1R AT1R β-arrestin biased Agonist Effects on Cardiac Performance Effects on HF model Effects on Ischemia Reperfusion Injury
20 Discovery of β-arrestin Purified βark (GRK2) loses ability to desensitize isolated β2-ar (Benovic et al 85, 86) Abundant retinal protein, 48 K protein or S Antigen works with rhodopsin kinase to deactivate rhodopsin renamed arrestin (Kuhn, et al 87) S antigen (48 kda protein) cloned (Shinohara et al 87) β-arrestin1 cloned (Lohse et al 90) β-arrestin2 cloned (Attramadal et al 92)
21 Arrestins AKA Distribution 7MSR Arrestin 1 (Visual Arrestin) Retinal rods Rhodopsin β-arrestin 1 (Arrestin 2) Ubiquitous Most β-arrestin 2 (Arrestin 3) Ubiquitous Most X Arrestin (Arrestin 4) Retinal cones Opsins Sigler PB & Schubert C, 2001 Structure, Vol. 9,
22 Role of β-arrestin Two Paradigms: Activation & Desensitization Adapted from Lefkowitz 2012 Nobel prize Lecture
23 Role of β-arrestin New Signaling Paradigm Adapted from Lefkowitz 2012 Nobel prize Lecture
24 β-arrestin Signaling of AT1R Xiao et al PNAS 2010
25 Protein kinases involved in β-arrestin mediated cellular signaling downstream of AT1aR Xiao et al PNAS 2010
26 GPCR in Heart RAS system Angiotensin II and AT1R β-arrestin Biased Agonism of AT1R AT1R β-arrestin biased Agonist Effects on Cardiac Performance Effects on HF model Effects on Ischemia Reperfusion Injury
27 Biased ligands and biased receptors N. Noor et al Journal of Molecular and Cellular Cardiology 2011
28 β-arrestin biased agonist
29 A biased ligand at the AT1AR signals only through β-arrestin Violin & Lefkowitz, TiPS 2007
30 β-arrestin biased agonist; SII Angiotensin II induced ERK phoaphorylation ; Gq-dependent and independent AT1R signaling Gitte et al Molecular & Cellular Proteomics 2010
31 TRV Family; Evidence of Biased Agonist TRV induced AT1R internalization Rat AT1aR fused to cyan fluorescent protein in HEK 293 cell Violin et al JPET 2010
32 TRV Family; Evidence of Biased Agonist chemiluminescent -galactosidase activity, Red; Ang II, Black; TRV TRV120023; Sar-Arg-Val-Tyr-Lys-His-Pro-Ala-OH TRV120026; Sar-Arg-Val-Tyr-Tyr-His-Pro-NH2 TRV120027; Sar-Arg-Val-Tyr-Ile-His-Pro-D-Ala-OH EC50 = 16nM, t1/2 = 16 min, Parenteral Use Violin et al JPET 2010
33 TRV Family; Evidence of Biased Agonist Chemiluminescent -galactosidase activity, Red; Ang II, Black; TRV Kim KS et al, AJP-Heart Circ Physiol 2012
34 GPCR in Heart RAS system Angiotensin II and AT1R β-arrestin Biased Agonism of AT1R AT1R β-arrestin biased Agonist Effects on Cardiac Performance Effects on HF model Effects on Ischemia Reperfusion Injury
35 Arrestin-2 mediated inotropic effect of AT1R in isolated cardiac myocyte GRK6 and β-arrestin 2-dependent PNAS, 2006
36 Biased Agonist of AT1R SII 1 Sar, 4 Ile, 8 Ile-Angiotensin II Low receptor binding affinity Not able to use in vivo experiment No in vivo data TRV023 Sar-Arg-Val-Tyr-Lys-His-Pro-Ala-OH MW=940.1 More potent β-arrestin biased agonist of AT1R
37 Effects on Cardiac Contractibility PV Loop Study- ESPVR (Ees) Kim KS et al AJP-Heart Circ Physiol 2012
38 Enhanced contractibility and cardiac function by TRV Family TRV TRV Violin et al JPET 2010, Kim KS et al AJP-Heart Circ Physiol 2012
39 GPCR in Heart RAS system Angiotensin II and AT1R β-arrestin Biased Agonism of AT1R AT1R β-arrestin biased Agonist Effects on Cardiac Performance Effects on HF model Effects on Ischemia Reperfusion Injury
40 β-arrestin biased agonist of AT1R
41 TRV in Canaine HF Model MAP, PCWP, CO Renal blood flow No change of plasma ANP & BNP Increased enos generation Vasodilation Reduction of cardiac preload & afterload Boerrigter et al Circ Heart Fail 2011
42 TRV120027; Human Trial (First in Man) To evaluate the hemodynamic effects of TRV027 To evaluate the safety and tolerability of an intravenous infusion of TRV Inclusion Criteria Ejection fraction <35% NYHA class 3 or 4 HF; indication for right-heart cath Systolic BP >100 mmhg, heart rate 90 bpm at rest O2 sat 94% (RA), scr 1.8 mg/dl (males) or 1.5 mg/dl (females) Baseline average PCWP 20 mmhg on 3 consecutive measures Soergel et al, ACC 2013
43 TRV120027; Human Trial (First in Man) 33 subjects participated at 15 centers in the US and Europe Soergel et al, ACC 2013
44 TRV027 reduces MAP and potentially PCWP in CHF subjects Soergel et al, ACC 2013
45 TRV027 did not adversely effect HR, CI, or biomarkers Soergel et al, ACC 2013
46 GPCR in Heart RAS system Angiotensin II and AT1R β-arrestin Biased Agonism of AT1R AT1R β-arrestin biased Agonist Effects on Cardiac Performance Effects on HF model Effects on Ischemia Reperfusion Injury
47 SII Reduced Ischemia Reperfusion Injury Ex vivo ischemia reperfusion injury model using langendorff system AngII ; 100nM, [SII]AngII; 18.7 μm in Langendorff perfusion buffer Hostrup et al Cell Physiol Biochem 2012
48 TRV enhances ERK1/2 and Akt signaling after ischemia reperfusion (IR) Kim KS et al AJP-Heart Circ Physiol 2012
49 IR-induced cardiomyocyte apoptosis was attenuated by TRV pretreatment Kim KS et al AJP-Heart Circ Physiol 2012
50 Summary AT1R β-arrestin biased Agonist Increase in cardiac performance and preserved stroke volume Decreased preload and afterload in HF Decreased apoptosis during acute cardiac injury
51 Conclusion β-arrestin biased agonism of AT1R Enhanced cardiac performance Cardioprotective effect during acute cardiac injury Target of new drug development in cardiovascular disease
52 Thank You for Your Attention
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