Academic Press is an imprint of Elsevier 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA 32, Jamestown Road, London NW1 7BY, UK The Boulevard, Langford Lane, Kidlington, Oxford, OX5 1GB, UK Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands First edition 2014 Copyright © 2014 Elsevier Inc All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: permissions@elsevier.com Alternatively you can submit your request online by visiting the Elsevier web site at http://elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-417197-8 ISSN: 1054-3589 For information on all Academic Press publications visit our website at store.elsevier.com Printed and bound in United States in America 14 15 16 10 PREFACE Constitutive activity, which is signaling in the absence of agonists, was first described in early 1980s in the type A g-aminobutyric receptor, an ion channel The recording of a single ion channel showed that it can, indeed, open in the absence of an agonist Ligands that decrease the elevated basal activity were then described for these receptors Very quickly, studies from Nobel Laureate Robert Lefkowitz’s laboratory showed that G protein-coupled receptors (GPCRs) could couple to G proteins in the absence of ligands, at least in reconstituted systems Finally in 1989, Costa and Herz demonstrated in neuroblastoma cells expressing d-opioid receptors endogenously, there is significant basal activity which can be decreased by some antagonists, the so-called “negative antagonists,” now commonly referred to as “inverse agonists.” Following these pioneering studies, together with the cloning of numerous GPCRs and their heterologous expression in cell lines, several important discoveries were made Mutations generated by site-directed mutagenesis can cause significant increase in basal activity, presumably by breaking interactions that constrain the wild-type receptor in inactive conformation Numerous studies utilized this strategy to gain insights into the structure of GPCRs before the crystal structures of GPCRs were reported Other studies used these data, together with homology modeling, after some of the crystal structures of GPCRs began to appear in the literature Some wild-type receptors have significant basal activity, which can be dramatically different even between closely related receptors Naturally occurring mutations in several GPCRs that either increase or decrease basal activity can cause significant human diseases, including cancer Highly constitutively active GPCRs in viruses also cause human diseases Transgenic animals expressing constitutively active mutant receptors present phenotypes that suggest constitutive activity has physiological relevance in vivo Receptor theory was modified to account for the constitutive activity A look back at the drugs that target GPCRs indeed reveal that the majority of the antagonists are inverse agonists, not neutral antagonists These are just some of the major advances and the field is still rapidly expanding In this volume, we tried to capture a glimpse of recent progress in several selected GPCRs The offerings include not only rhodopsin, one of the most extensively studied and the first example of genetic mutations causing ix x Preface human disease, but also the glycoprotein hormone receptors, the cannabinoid receptor, the melanocortin-4 receptor, the angiotensin type receptor, the dopamine receptors, the chemokine receptors, and a chemosensory receptor, the bitter taste receptor We also recruited a chapter on the constitutive activity of a nuclear receptor, the androgen receptor, and two chapters on ion channels I thank Dr S.J Enna, the Series Editor, for his support for this volume, and Ms Lynn LeCount, the Managing Editor, for everything she did to make sure this volume moves along as scheduled I am very grateful to all the contributors, who are all busy scientists with numerous commitments, for taking the time to write their excellent contributions I anticipate this volume will stimulate further research in this fascinating field of constitutive activity YA-XIONG TAO Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA Volume 70 Editor CONTRIBUTORS Issam Abu-Taha Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Essen, Germany Awatif Albaker Ottawa Hospital Research Institute (Neuroscience Program), and Departments of Medicine, Cellular & Molecular Medicine, Psychiatry, University of Ottawa, Ottawa, Ontario, Canada Rajinder P Bhullar Department of Oral Biology, University of Manitoba, Winnipeg, Manitoba, Canada Heike Biebermann Institute of Experimental Pediatric Endocrinology, Charite-Universitaătsmedizin Berlin, Berlin, Germany George Bousfield Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France, and Department of Biological Sciences, Wichita State University, Wichita, Kansas, USA Siu Chiu Chan Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA Prashen Chelikani Department of Oral Biology, University of Manitoba, Winnipeg, Manitoba, Canada Scott M Dehm Masonic Cancer Center, and Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA James A Dias Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France, and Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York, USA Dobromir Dobrev Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Essen, Germany Colleen A Flanagan School of Physiology and Medical Research Council Receptor Biology Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Private Bag 3, Wits, South Africa Tung M Fong Forest Research Institute, Jersey City, New Jersey, USA Xinbing Han Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA xi xii Contributors Jordi Heijman Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Essen, Germany Ilpo Huhtaniemi Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France, and Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom Sadashiva S Karnik Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA Gunnar Kleinau Institute of Experimental Pediatric Endocrinology, Charite-Universitaătsmedizin Berlin, Berlin, Germany Caroline Lefebvre Ottawa Hospital Research Institute (Neuroscience Program), and Departments of Medicine, Cellular & Molecular Medicine, Psychiatry, University of Ottawa, Ottawa, Ontario, Canada Dori Miller Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA Paul Shin-Hyun Park Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA Bianca Plouffe Department of Biochemistry, Universite´ de Montre´al, and Institut de recherche en immunologie, cancer, Montre´al, Que´bec, Canada Sai P Pydi Department of Oral Biology, University of Manitoba, Winnipeg, Manitoba, Canada Eric Reiter Studium Consortium for Research and Training in Reproductive Sciences (sCORTS); BIOS Group, INRA, UMR85, Unite´ Physiologie de la Reproduction et des Comportements; CNRS, UMR7247, Nouzilly, and Universite´ Franc¸ois Rabelais, Tours, France Ya-Xiong Tao Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA Mario Tiberi Ottawa Hospital Research Institute (Neuroscience Program), and Departments of Medicine, Cellular & Molecular Medicine, Psychiatry, University of Ottawa, Ottawa, Ontario, Canada Contributors xiii Alfredo Ulloa-Aguirre Studium Consortium for Research and Training in Reproductive Sciences (sCORTS), Tours, France, and Research Support Network, Instituto Nacional de Ciencias Me´dicas y Nutricio´n “Salvador Zubira´n” and Universidad Nacional Auto´noma de Me´xico, Me´xico D.F., Mexico Hamiyet Unal Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA Niels Voigt Faculty of Medicine, Institute of Pharmacology, University Duisburg-Essen, Essen, Germany Lili Wang Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA Boyang Zhang Ottawa Hospital Research Institute (Neuroscience Program), and Departments of Medicine, Cellular & Molecular Medicine, Psychiatry, University of Ottawa, Ottawa, Ontario, Canada Juming Zhong Department of Anatomy, Physiology & Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA CHAPTER ONE Constitutively Active Rhodopsin and Retinal Disease Paul Shin-Hyun Park1 Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, Ohio, USA Corresponding author: e-mail address: paul.park@case.edu Contents Introduction Rhodopsin Activity 2.1 Physiology of rhodopsin activity 2.2 Molecular switches that lock rhodopsin in an inactive state Constitutive Activity in Rhodopsin that Causes Disease 3.1 Leber congenital amaurosis and vitamin A deficiency 3.2 Congenital night blindness 3.3 Retinitis pigmentosa How Constitutive Activity Can Cause Different Phenotypes 4.1 Different levels of activity as an underlying cause of different phenotypes 4.2 Do all constitutively active mutants adopt the same active-state conformation? Conclusion Conflict of Interest Acknowledgments References 5 10 12 12 15 19 22 22 23 26 27 27 27 Abstract Rhodopsin is the light receptor in rod photoreceptor cells of the retina that initiates scotopic vision In the dark, rhodopsin is bound to the chromophore 11-cis retinal, which locks the receptor in an inactive state The maintenance of an inactive rhodopsin in the dark is critical for rod photoreceptor cells to remain highly sensitive Perturbations by mutation or the absence of 11-cis retinal can cause rhodopsin to become constitutively active, which leads to the desensitization of photoreceptor cells and, in some instances, retinal degeneration Constitutive activity can arise in rhodopsin by various mechanisms and can cause a variety of inherited retinal diseases including Leber congenital amaurosis, congenital night blindness, and retinitis pigmentosa In this review, the molecular and structural properties of different constitutively active forms of rhodopsin are overviewed, and the possibility that constitutive activity can arise from different active-state conformations is discussed Advances in Pharmacology, Volume 70 ISSN 1054-3589 http://dx.doi.org/10.1016/B978-0-12-417197-8.00001-8 # 2014 Elsevier Inc All rights reserved Paul Shin-Hyun Park ABBREVIATIONS CNB congenital night blindness CP cytoplasmic loop EC extracellular loop EPR electron paramagnetic resonance GPCR G protein-coupled receptor H8 amphipathic alpha helix LCA Leber congenital amaurosis LRAT lecithin retinol acyltransferase MI metarhodopsin I MII metarhodopsin II R inactive state R* active state RIS rod inner segment(s) ROS rod outer segment(s) RP retinitis pigmentosa RPE65 retinal pigment epithelium-specific 65 kDa protein TM transmembrane alpha helix lmax maximal absorbance of light INTRODUCTION Rhodopsin is a member of the G protein-coupled receptor (GPCR) family of membrane proteins Bovine rhodopsin was the first GPCR to have its primary, secondary, and tertiary structures determined (Hargrave et al., 1983; Nathans & Hogness, 1983; Ovchinnikov Yu, 1982; Palczewski et al., 2000; Schertler, Villa, & Henderson, 1993) These studies revealed a structure with seven transmembrane alpha helices (TM1–TM7) connected by extracellular (EC1–EC3) and cytoplasmic (CP1–CP3) loops and an amphipathic alpha helix (H8) that sits parallel to the membrane surface (Fig 1.1) The human gene for rhodopsin was isolated and sequenced in the mid-1980s (Nathans & Hogness, 1984) The rhodopsin gene is a hot spot for inherited mutations causing retinal disease (Mendes, van der Spuy, Chapple, & Cheetham, 2005; Nathans, Merbs, Sung, Weitz, & Wang, 1992; Stojanovic & Hwa, 2002) Rhodopsin is the light receptor that initiates scotopic vision in rod photoreceptor cells of the retina upon photon capture The receptor is embedded at a high concentration in disk membranes of rod outer segments (ROS) (Fig 1.2A) Intense efforts to understand the structure and function of this light receptor have been ongoing for quite some time, especially after the initial discovery that a single point mutation in the rhodopsin gene causes retinitis pigmentosa (RP) (Dryja et al., 1990), a retinal degenerative disease Even with Constitutively Active Rhodopsin A NH2 M N R S F G S P 10 190 T P Y Y T L V Y F D 30 K Q P Y E F N P G E I Y P 180 G E L Y L G P E A 280 E C S CQ I V F V F Q G S P G Y Y N N H S 100 R 200 P T W G F T S S N H L Q F W G I Y E S 40 F S G C110 G S F P M T N F A L A 270 Y L I L V A V F E I A T S G Y A 170 L P Y M 290 M S M Y P F A F P T I T F F 90 F A A 210 P A L L V T V G G 120 W C C I I V V H F F L A L 50 L G G F T A A L 260 V M L G F K S I A E M V 160 I A F L F A P I W T L 300 M A V P I DA WS M I I I F A I Y 220 I N 80 V L 130 F N I F V V V M A L G M V L P V L F C 60 T L 250 R N L I I A A T Y Y I Y V L I V H I E R N 150 G M K E E T V Y E Y Q A N L G V V M K Q L P Q T V 140 310 N F I C C F M H V T T 70 C L T 320 G R K R K A F K L R K K Q N T F 230 T 240 S C V N P M S N E P K Q Q E A A A Q L 330 G TM1 TM2 TM3 TM4 TM5 TM6 TM7 D D 340 E HOOC A P A V Q S T E T K S V T A S A 20 V Extracellular Cytoplasmic V G T A N B Figure 1.1 Structure of rhodopsin (A) The secondary structure of human rhodopsin is shown with residues causing constitutive activity and retinal disease when mutated, highlighted in black (Gly90, Thr94, Ser186, Asp190, Ala292, and Ala295), except for Lys296 Residues forming molecular switches are colored as follows: green (dark gray in the print version; Glu113, Glu181, and Lys296), protonated Schiff base switch; yellow (very light gray in the print version; Cys264, Trp265, Pro267, and Ala269), CWxP motif switch; cyan (light gray in the print version; Glu122, Trp126, and His211), TM3–TM5 hydrogen bond network switch; blue (dark gray in the print version; Asn55, Asp83, Ala298, Ala299, Asn302, Pro303, Tyr306, and Phe313), NPxxY motif switch; red (dark gray in the print version; Glu134, Arg135, Tyr136, Glu247, an Thr251), D(E)RY motif switch Residues forming the CWxP, NPxxY, and D(E)RY motifs are highlighted in bold (B) Crystal structures of the inactive state of bovine rhodopsin (colored, PDB: 1U19) and the MII state of bovine rhodopsin (gray, PDB: 3PXO) were aligned with PyMOL Residues causing constitutive activity and retinal disease when mutated are depicted as black spheres 11-cis Retinal is depicted as pink spheres Helices in the inactive-state structure are colored as follows: blue (dark gray in the print version), TM1; cyan (light gray in the print version), TM2; green (dark gray in the print version), TM3; lime green (gray in the print version), TM4; yellow (very light gray in the print version), TM5; orange (dark gray in the print version), TM6; red (dark gray in the print version), TM7; purple (dark gray in the print version), H8 these efforts, the mechanistic description of rhodopsin activity is incomplete Since the initial discovery, more than 100 point mutations have been discovered in the rhodopsin gene that cause retinal disease (Garriga & Manyosa, 2002; Mendes et al., 2005; Nathans et al., 1992; Stojanovic & Hwa, 2002) Under normal function, rhodopsin is covalently bound to 11-cis retinal and is inactive in the dark (Fig 1.2B) Rhodopsin must be activated by light to initiate vision Constitutive activity in rhodopsin (i.e., receptor activation in the absence of light stimulation) can arise because of mutation or the absence of bound 11-cis retinal and can cause a range of inherited retinal diseases including Leber congenital amaurosis (LCA), congenital night blindness (CNB), and RP (Rao, Cohen, & Oprian, 1994; Robinson, Cohen, Zhukovsky, & Oprian, Paul Shin-Hyun Park Rod photoreceptor cell Dark A Light Transducin Arrestin Outer segment Inner segment/perinuclear region B Rhodopsin MII Light Light Rho MII α β γ MII MII P P P Arr Ops GTP GDP 11-cis Retinal Figure 1.2 Rod photoreceptor cells and phototransduction (A) Cartoon depiction of a rod photoreceptor cell The cartoon of the cell on the left shows the structure of a rod photoreceptor cell with disk membranes in the ROS and mitochondria, Golgi apparatus, endoplasmic reticulum, and nucleus in the RIS/perinuclear region Rhodopsin is embedded in disk membranes of the outer segment The cartoons of the cell in the middle and on the right illustrate the levels of transducin (green; gray in the print version) and arrestin (blue; black in the print version) in the ROS and RIS/perinuclear region in the dark and in the light (B) Life cycle of rhodopsin Rhodopsin is covalently bound to 11-cis retinal in the dark Light isomerizes 11-cis retinal to all-trans retinal, which promotes the activation of rhodopsin and formation of the MII state MII binds and activates the heterotrimeric G protein transducin (green; light gray in the print version) to initiate phototransduction MII is inactivated via phosphorylation by rhodopsin kinase and the binding of arrestin (blue; dark gray in the print version) The MII state decays to opsin upon release of all-trans retinal from the chromophore-binding pocket Opsin must reconstitute with 11-cis retinal to regenerate rhodopsin 404 Niels Voigt et al Extracellular space TTP Selectivity filter M1: Outer helix M2: Inner helix Cytosol G loop gate βγ, PIP2) (Gβ Inner helix gate C-terminus N-terminus E224 D259 E299 E231 D266 E306 Chloroquine Figure 13.6 Crystal structure of an IK,ACh channel For clarity, only two (Kir3.2) subunits are illustrated The right panel shows a side view of channel depicted on the left The IK,ACh channel consists of two pores in series One transmembrane pore is formed by the M2 inner helix domains and a second pore is formed by cytoplasmic domains The binding sites of phosphatidylinositol 4,5-bisphosphate (PIP2) and Gbg-subunits are indicated The selective IK,ACh blocker tertiapin (TTP) binds on the external vestibule of the transmembrane domain, whereas the antiarrhythmic agent chloroquine binds on the center of the cytoplasmic pore and blocks the IK,ACh channel by interacting with acidic residues (primarily E224, D259, and E299) (Protein Data Bank (PDB) ID code: 3SYO) Replotted with permission from Dobrev et al (2012) rectifier K+ channels by interacting with the center of the cytoplasmic conduction pore (Noujaim et al., 2010) Despite these important proceedings in the development of IK,ACh modulators, their unspecific side effects arising from the blockade of agonist-dependent IK,ACh in the central nervous system and peripheral tissue (sinoatrial node, gastrointestinal tract, and genitourinary system) may limit the value of such therapeutic approaches An improved understanding of the molecular structure of the IK,ACh channel and the molecular basis of constitutively active IK,ACh channels will probably allow the development of atrial-selective and pathology-specific drugs for the treatment of AF patients CONCLUSION Development of abnormal constitutively active IK,ACh has been shown to play an important role in electrical remodeling associated with heart diseases such as atrial fibrillation Recent work has provided insights into the potential underlying mechanisms, which may constitute future therapeutic targets Acetylcholine-Activated Potassium Current 405 CONFLICT OF INTEREST The authors have no conflicts of interest to declare ACKNOWLEDGMENTS This work is supported by the Foundation Leducq (European-North American Atrial Fibrillation Research Alliance, ENAFRA, grant 07CVD03), the German Federal Ministry of Education and Research through DZHK (German Centre for Cardiovascular Research), the Deutsche Forschungsgemeinschaft (Do 769/1-3), and the European Union (European Network for Translational Research in Atrial Fibrillation, EUTRAF, grant 261057) REFERENCES Abu-Taha, I., Voigt, N., Nattel, S., Wieland, T., & Dobrev, D (2013) Nucleoside diphosphate kinase B is a novel receptor-independent activator of G-protein signaling in clinical and experimental atrial fibrillation Naunyn-Schmiedeberg’s Archives of Pharmacology, 386, S3 Beckmann, C., Rinne, A., Littwitz, C., Mintert, E., Bosche, L I., Kienitz, M C., et al (2008) G protein-activated (GIRK) current in rat ventricular myocytes is masked by constitutive inward rectifier current (IK1) Cellular Physiology and Biochemistry, 21, 259–268 Calloe, K., Goodrow, R., Olesen, S P., Antzelevitch, C., & Cordeiro, J M (2013) Tissuespecific effects of acetylcholine in the canine heart American Journal of Physiology Heart and Circulatory Physiology, 305, H66–H75 Cha, T J., Ehrlich, J R., Chartier, D., Qi, X Y., Xiao, L., & Nattel, S (2006) Kir3-based inward rectifier potassium current: Potential role in atrial tachycardia remodeling effects on atrial repolarization and arrhythmias Circulation, 113, 1730–1737 Cho, H., Nam, G B., Lee, S H., Earm, Y E., & Ho, W K (2001) Phosphatidylinositol 4,5-bisphosphate is acting as a signal molecule in a1-adrenergic pathway via the modulation of acetylcholine-activated K+ channels in mouse atrial myocytes The Journal of Biological Chemistry, 276, 159–164 Christ, T., Wettwer, E., Voigt, N., Hala, O., Radicke, S., Matschke, K., et al (2008) Pathology-specific effects of the IKur/Ito/IK,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation British Journal of Pharmacology, 154, 1619–1630 Cui, S., Ho, W K., Kim, S T., & Cho, H (2010) Agonist-induced localization of Gq-coupled receptors and G protein-gated inwardly rectifying K+ (GIRK) channels to caveolae determines receptor specificity of phosphatidylinositol 4,5-bisphosphate signaling The Journal of Biological Chemistry, 285, 41732–41739 Dobrev, D., Carlsson, L., & Nattel, S (2012) Novel molecular targets for atrial fibrillation therapy Nature Reviews Drug Discovery, 11, 275–291 Dobrev, D., Friedrich, A., Voigt, N., Jost, N., Wettwer, E., Christ, T., et al (2005) The G protein-gated potassium current IK,ACh is constitutively active in patients with chronic atrial fibrillation Circulation, 112, 3697–3706 Dobrev, D., & Nattel, S (2010) New antiarrhythmic drugs for treatment of atrial fibrillation Lancet, 375, 1212–1223 Dobrev, D., Voigt, N., & Nattel, S (2013) Cholinergic and constitutive regulation of atrial potassium channels In D Zipes & J Jalife (Eds.), Cardiac electrophysiology: From cell to bedside Philadelphia, PA: Elsevier ISBN: 978-1-4557-2856-5 Dobrev, D., Wettwer, E., Himmel, H M., Kortner, A., Kuhlisch, E., Schuler, S., et al (2000) G-Protein b3-subunit 825T allele is associated with enhanced human atrial inward rectifier potassium currents Circulation, 102, 692–697 406 Niels Voigt et al Ehrlich, J R., Cha, T J., Zhang, L., Chartier, D., Villeneuve, L., Hebert, T E., et al (2004) Characterization of a hyperpolarization-activated time-dependent potassium current in canine cardiomyocytes from pulmonary vein myocardial sleeves and left atrium The Journal of Physiology, 557, 583–597 Gaborit, N., Le Bouter, S., Szuts, V., Varro, A., Escande, D., Nattel, S., et al (2007) Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart The Journal of Physiology, 582, 675–693 Grandi, E., Pandit, S V., Voigt, N., Workman, A J., Dobrev, D., Jalife, J., et al (2011) Human atrial action potential and Ca2+ model: Sinus rhythm and chronic atrial fibrillation Circulation Research, 109, 1055–1066 Heijman, J., Voigt, N., & Dobrev, D (2013) New directions in antiarrhythmic drug therapy for atrial fibrillation Future Cardiology, 9, 71–88 Heijman, J., Voigt, N., Nattel, S., & Dobrev, D (2014) Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance and progression Circulation Research, 114(9), 1483–1499 http://dx.doi.org/10.1161/CIRCRESAHA.114.302226 Hibino, H., Inanobe, A., Furutani, K., Murakami, S., Findlay, I., & Kurachi, Y (2010) Inwardly rectifying potassium channels: Their structure, function, and physiological roles Physiological Reviews, 90, 291–366 Hill, J J., & Peralta, E G (2001) Inhibition of a Gi-activated potassium channel (GIRK1/4) by the Gq-coupled M1 muscarinic acetylcholine receptor The Journal of Biological Chemistry, 276, 5505–5510 Himmel, H M., Meyer Zu Heringdorf, D., Graf, E., Dobrev, D., Kortner, A., Schuler, S., et al (2000) Evidence for Edg-3 receptor-mediated activation of IK.ACh by sphingosine1-phosphate in human atrial cardiomyocytes Molecular Pharmacology, 58, 449–454 Hippe, H J., Lutz, S., Cuello, F., Knorr, K., Vogt, A., Jakobs, K H., et al (2003) Activation of heterotrimeric G proteins by a high energy phosphate transfer via nucleoside diphosphate kinase (NDPK) B and Gb subunits The Journal of Biological Chemistry, 278, 7227–7233 Ho, I H., & Murrell-Lagnado, R D (1999) Molecular mechanism for sodium-dependent activation of G protein-gated K+ channels The Journal of Physiology, 520(Pt 3), 645–651 Huang, C L., Feng, S., & Hilgemann, D W (1998) Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbg Nature, 391, 803–806 Ito, H., Ono, K., & Noma, A (1994) Background conductance attributable to spontaneous opening of muscarinic K+ channels in rabbit sino-atrial node cells The Journal of Physiology, 476, 55–68 Jan, L Y., & Jan, Y N (2000) Heartfelt crosstalk: Desensitization of the GIRK current Nature Cell Biology, 2, E165–E167 Jin, W., Klem, A M., Lewis, J H., & Lu, Z (1999) Mechanisms of inward-rectifier K+ channel inhibition by tertiapin-Q Biochemistry, 38, 14294–14301 Jin, W., & Lu, Z (1998) A novel high-affinity inhibitor for inward-rectifier K+ channels Biochemistry, 37, 13291–13299 Jin, W., & Lu, Z (1999) Synthesis of a stable form of tertiapin: A high-affinity inhibitor for inward-rectifier K+ channels Biochemistry, 38, 14286–14293 Kobrinsky, E., Mirshahi, T., Zhang, H., Jin, T., & Logothetis, D E (2000) Receptormediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization Nature Cell Biology, 2, 507–514 Koumi, S., & Wasserstrom, J A (1994) Acetylcholine-sensitive muscarinic K+ channels in mammalian ventricular myocytes The American Journal of Physiology, 266, H1812–H1821 Kovoor, P., Wickman, K., Maguire, C T., Pu, W., Gehrmann, J., Berul, C I., et al (2001) Evaluation of the role of IK,ACh in atrial fibrillation using a mouse knockout model Journal of the American College of Cardiology, 37, 2136–2143 Acetylcholine-Activated Potassium Current 407 Krapivinsky, G., Gordon, E A., Wickman, K., Velimirovic, B., Krapivinsky, L., & Clapham, D E (1995) The G-protein-gated atrial K + channel IK,ACh is a heteromultimer of two inwardly rectifying K+-channel proteins Nature, 374, 135–141 Kurachi, Y., Nakajima, T., Ito, H., & Sugimoto, T (1989) AN-132, a new class I antiarrhythmic agent, depresses the acetylcholine-induced K+ current in atrial myocytes European Journal of Pharmacology, 165, 319–322 Kurachi, Y., Nakajima, T., & Sugimoto, T (1986) On the mechanism of activation of muscarinic K+ channels by adenosine in isolated atrial cells: Involvement of GTP-binding proteins Pfluăgers Archiv, 407, 264274 Kurachi, Y., Nakajima, T., & Sugimoto, T (1987) Quinidine inhibition of the muscarine receptor-activated K+-channel current in atrial cells of guinea pig Naunyn-Schmiedeberg’s Archives of Pharmacology, 335, 216–218 Levay, M., Krobert, K A., Wittig, K., Voigt, N., Bermudez, M., Wolber, G., et al (2013) NSC23766, a widely used inhibitor of Rac1 activation, additionally acts as a competitive antagonist at muscarinic acetylcholine receptors Journal of Pharmacology and Experimental Therapeutics, 347, 69–79 Liang, B., Nissen, J D., Laursen, M., Wang, X., Skibsbye, L., Hearing, M C., et al (2014) G-protein-coupled inward rectifier potassium current contributes to ventricular repolarization Cardiovascular Research, 101, 175–184 ¨ ber humorale U ¨ bertragbarkei der Herznervenwirkung Pflu¨gers Archiv, Loewi, O (1921) U 189, 239–242 Lutz, S., Mura, R., Baltus, D., Movsesian, M., Kubler, W., & Niroomand, F (2001) Increased activity of membrane-associated nucleoside diphosphate kinase and inhibition of cAMP synthesis in failing human myocardium Cardiovascular Research, 49, 48–55 Makary, S., Voigt, N., Maguy, A., Wakili, R., Nishida, K., Harada, M., et al (2011) Differential protein kinase C isoform regulation and increased constitutive activity of acetylcholineregulated potassium channels in atrial remodeling Circulation Research, 109, 1031–1043 Mark, M D., & Herlitze, S (2000) G-protein mediated gating of inward-rectifier K+ channels European Journal of Biochemistry, 267, 5830–5836 Medina, I., Krapivinsky, G., Arnold, S., Kovoor, P., Krapivinsky, L., & Clapham, D E (2000) A switch mechanism for Gbg activation of IK,ACh The Journal of Biological Chemistry, 275, 29709–29716 Meyer, T., Wellner-Kienitz, M C., Biewald, A., Bender, K., Eickel, A., & Pott, L (2001) Depletion of phosphatidylinositol 4,5-bisphosphate by activation of phospholipase C-coupled receptors causes slow inhibition but not desensitization of G protein-gated inward rectifier K+ current in atrial myocytes The Journal of Biological Chemistry, 276, 5650–5658 Milnes, J T., Madge, D J., & Ford, J W (2012) New pharmacological approaches to atrial fibrillation Drug Discovery Today, 17, 654–659 Mintert, E., Bosche, L I., Rinne, A., Timpert, M., Kienitz, M C., Pott, L., et al (2007) Generation of a constitutive Na+-dependent inward-rectifier current in rat adult atrial myocytes by overexpression of Kir3.4 The Journal of Physiology, 585, 3–13 Nattel, S., Voigt, N., & Dobrev, D (2013) Molecular pathophysiology of atrial fibrillation In D Zipes & J Jalife (Eds.), Cardiac electrophysiology: From cell to bedside Philadelphia, PA: Elsevier ISBN: 978-1-4557-2856-5 Nikolov, E N., & Ivanova-Nikolova, T T (2004) Coordination of membrane excitability through a GIRK1 signaling complex in the atria The Journal of Biological Chemistry, 279, 23630–23636 Niroomand, F., Mura, R., Jakobs, K H., Rauch, B., & Kubler, W (1997) Receptorindependent activation of cardiac adenylyl cyclase by GDP and membrane-associated nucleoside diphosphate kinase A new cardiotonic mechanism? Journal of Molecular and Cellular Cardiology, 29, 1479–1486 408 Niels Voigt et al Noma, A., & Trautwein, W (1978) Relaxation of the ACh-induced potassium current in the rabbit sinoatrial node cell Pfluăgers Archiv, 377, 193200 Noujaim, S F., Stuckey, J A., Ponce-Balbuena, D., Ferrer-Villada, T., Lopez-Izquierdo, A., Pandit, S., et al (2010) Specific residues of the cytoplasmic domains of cardiac inward rectifier potassium channels are effective antifibrillatory targets The FASEB Journal, 24, 4302–4312 Ramu, Y., Klem, A M., & Lu, Z (2004) Short variable sequence acquired in evolution enables selective inhibition of various inward-rectifier K+ channels Biochemistry, 43, 10701–10709 Ramu, Y., Xu, Y., & Lu, Z (2008) Engineered specific and high-affinity inhibitor for a subtype of inward-rectifier K+ channels Proceedings of the National Academy of Sciences of the United States of America, 105, 10774–10778 Rishal, I., Porozov, Y., Yakubovich, D., Varon, D., & Dascal, N (2005) Gbg-dependent and Gbg-independent basal activity of G protein-activated K+ channels The Journal of Biological Chemistry, 280, 16685–16694 Riven, I., Iwanir, S., & Reuveny, E (2006) GIRK channel activation involves a local rearrangement of a preformed G protein channel complex Neuron, 51, 561–573 Rosenhouse-Dantsker, A., Sui, J L., Zhao, Q., Rusinova, R., Rodriguez-Menchaca, A A., Zhang, Z., et al (2008) A sodium-mediated structural switch that controls the sensitivity of Kir channels to PtdIns(4,5)P(2) Nature Chemical Biology, 4, 624–631 Rubinstein, M., Peleg, S., Berlin, S., Brass, D., & Dascal, N (2007) Gai3 primes the G protein-activated K + channels for activation by coexpressed Gbg in intact Xenopus oocytes The Journal of Physiology, 581, 17–32 Sakmann, B., Noma, A., & Trautwein, W (1983) Acetylcholine activation of single muscarinic K+ channels in isolated pacemaker cells of the mammalian heart Nature, 303, 250–253 Shui, Z., Boyett, M R., & Zang, W J (1997) ATP-dependent desensitization of the muscarinic K+ channel in rat atrial cells The Journal of Physiology, 505(Pt 1), 77–93 Steinberg, S F (2008) Structural basis of protein kinase C isoform function Physiological Reviews, 88, 1341–1378 Voigt, N., & Dobrev, D (2011) Ion channel remodeling in atrial fibrillation European Cardiology, 7, 97–103 Voigt, N., Friedrich, A., Bock, M., Wettwer, E., Christ, T., Knaut, M., et al (2007) Differential phosphorylation-dependent regulation of constitutively active and muscarinic receptor-activated IK,ACh channels in patients with chronic atrial fibrillation Cardiovascular Research, 74, 426–437 Voigt, N., Heijman, J., Trausch, A., Mintert-Jancke, E., Pott, L., Ravens, U., et al (2013) Impaired Na+-dependent regulation of acetylcholine-activated inward-rectifier K+ current modulates action potential rate dependence in patients with chronic atrial fibrillation Journal of Molecular and Cellular Cardiology, 61, 142–152 Voigt, N., Maguy, A., Yeh, Y H., Qi, X., Ravens, U., Dobrev, D., et al (2008) Changes in IK,ACh single-channel activity with atrial tachycardia remodelling in canine atrial cardiomyocytes Cardiovascular Research, 77, 35–43 Voigt, N., Makary, S., Nattel, S., & Dobrev, D (2010) Voltage-clamp-based methods for the detection of constitutively active acetylcholine-gated IK,ACh channels in the diseased heart Methods in Enzymology, 484, 653–675 Voigt, N., Rozmaritsa, N., Trausch, A., Zimniak, T., Christ, T., Wettwer, E., et al (2010) Inhibition of IK,ACh current may contribute to clinical efficacy of class I and class III antiarrhythmic drugs in patients with atrial fibrillation Naunyn-Schmiedeberg’s Archives of Pharmacology, 381, 251–259 Voigt, N., Trausch, A., Knaut, M., Matschke, K., Varro, A., Van Wagoner, D R., et al (2010) Left-to-right atrial inward rectifier potassium current gradients in patients with Acetylcholine-Activated Potassium Current 409 paroxysmal versus chronic atrial fibrillation Circulation Arrhythmia and Electrophysiology, 3, 472–480 Wakili, R., Voigt, N., Kaab, S., Dobrev, D., & Nattel, S (2011) Recent advances in the molecular pathophysiology of atrial fibrillation The Journal of Clinical Investigation, 121, 2955–2968 Whorton, M R., & MacKinnon, R (2011) Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium Cell, 147, 199–208 Wieland, T (2007) Interaction of nucleoside diphosphate kinase B with heterotrimeric G protein bg dimers: Consequences on G protein activation and stability NaunynSchmiedeberg’s Archives of Pharmacology, 374, 373–383 Yamada, M., Ho, Y K., Lee, R H., Kontanill, K., Takahashill, K., Katadall, T., et al (1994) Muscarinic K+ channels are activated by bg subunits and inhibited by the GDP-bound form of a subunit of transducin Biochemical and Biophysical Research Communications, 200, 1484–1490 Yamada, M., Inanobe, A., & Kurachi, Y (1998) G protein regulation of potassium ion channels Pharmacological Reviews, 50, 723–760 INDEX Note: Page numbers followed by “f ” indicate figures and “t ” indicate tables A Abiraterone, 351, 354 Acetylcholine-activated inward rectifier K+ current (IK,ACh) action potential duration (APD), 403–404 phosphatidylinositol 4,5-bisphosphate (PIP2) and Na+ regulation, 399–401 phosphorylation, 401–402 receptor-independent activity, G proteins Gαi and Gβγ-subunit, 397 nucleoside diphosphate kinase (NDPK) B, 397–399 remodeling process, 395f, 396 type muscarinic acetylcholine receptors (M2 receptors), 395–396 Action potential duration (APD), 403–404 Adult cardiac hypertrophy induction model, 169–170 Agouti-related protein (AgRP), 136–137 extracellular signal-regulated kinase (ERK) 1/2 signaling pathway, 142–144, 143f Gs-cAMP signaling pathway, 139, 140–141, 140f in vivo relevance of, 144–146 Androgen receptor (AR) biochemical properties DNA-binding domain, 334 hinge region, 334 ligand-binding domain (LBD), 334–335 NH2-terminal domain, 331–333 TAU1 domain, 331–333 castration-resistant prostate cancer (CRPC), 330–331 constitutive/ligand-hypersensitive activity, 355, 356f coregulators FKBP5 gene, 338 H3K4 methylation, 340 LSD1 and JMJD2C, 339–340 p300 and CBP, 339 steroid receptor coactivator (SRC), 338–339 cytokines and inflammatory signaling, 337–338 gene amplification and overexpression, 340 growth factor signaling pathways, 335–337 nuclear receptor (NR), 329 point mutations, 341–342 prostate cancer (PCa), 328–329 abiraterone, 351 binding function (BF3) inhibitors, 351–352 biomarkers, 353–355 DNA-binding domain, 352–353 enzalutamide and ARN-509, 351 NH2-terminal domain, 353 regulation and function, 330–331 role of, 328–329 splice variants (AR-Vs) clinical relevance, 346–347 constitutive transcriptional activity, 343–344 coregulators interaction, 348–349 gene targets, 349–350 genomic alteration, 344–345 identification and origin, 342–343 pioneer factors, 347–348 testosterone, 329 Angiotensin II type (AT1) receptor adult cardiac hypertrophy induction model, 169–170 angiotensinergic activation, vascular endothelium, 165–166 autoantibody activation, 164–165 complex mechanism aspects, 160–161 411 412 Angiotensin II type (AT1) receptor (Continued ) constraints, 161 desensitization and recycling kinetics, 161–162 factors, 157–158 hypersympathetic vasomotor tone model, 168–169 inverse and partial agonists, 162–163 in vivo activation, 163–164 low-renin hypertension model, 166–168 physiological and pathological process, 157 renal proximal tubule, 169 site-directed mutagenesis, 158–160 somatic mutation, 158 stretch activation, 165 weak constitutive activation, 160 B Bitter taste receptors (T2Rs) constitutively active mutants (CAMs) antagonists and inverse agonists, 318–319 calcium mobilization assay, 313 competition dose–response assays, 318 definition, 311–312 D/ERY motif, 312 downstream cellular signal, 318–319 experimental methods and detection systems, 318–319 hyperresponsive/hyporesponsive types, 312, 312f inositol triphosphate (IP3) assay, 314–315 intracellular loop (ICL3), 316–318 molecular modeling, 315 normoresponsive/nonmoresponsive types, 312, 312f δ opioid and β2-adrenergic receptors (ADRB2), 311–312 receptor density effect, 313–314, 314f transmembrane (TM) domain, 315–316 expression and localization bitter taste sensing genes, 306–307 cholinergic brush cells and regulate respiratory rate, 307 Index extraoral tissues, 307 nongustatory tissues, 307, 308t SCCs and regulate airway reflex, 307 mechanism highly conserved TM residues, 310–311 T2R-specific residues, 311 signal transduction, 305–306 taste sensory proteins, 304–305, 305f transient receptor potential channel M5 (TRPM5), 305–306 Brugada syndrome (BrS) frame-shift mutation, 380 functional characteristics, 381 history, 380 loss of function mechanism, 381 missense mutation, 380 splice-donor mutation, 380 treatment, 382–383 C CAMs See Constitutively active mutants (CAMs) Cannabinoid receptors classical receptor occupancy, 122 conformational selection theory, 122 constitutive activity agonist, inverse and neutral antagonist, 123–124 vs constitutive agonist tone, 124–126 in vitro cell-based assay, 126–128 exogenous agonists, 122 SR141716A, AM251, and MK-0364, 129–130 thermodynamics, 122–123 Cardiac sodium channels Brugada syndrome (BrS) frame-shift mutation, 380 functional characteristics, 381 history, 380 loss of function mechanism, 381 missense mutation, 380 splice-donor mutation, 380 treatment, 382–383 depolarization phases, 368–369 excitation-contraction coupling, 368 long QT syndrome (LQTS) Index action potential, electrocardiogram (ECG), and currents, 371f diagnosis, 378–379 gain-of-function mechanisms, 377 heterologous expression and electrophysiological measurements, 375–376 hinged-lid model, 376–377 identical intragenic deletions and missense mutations, 374–375 inherited/acquired disorder, 374 multiple peptide segments, 376–377 prolonged QT interval, 374 treatment, 379–380 types, 374 plateau phases, 368–369 progressive cardiac conduction disease (PCCD), 383 repolarization phases, 368–369 resting membrane potential phases, 368–369 sick sinus syndrome, 383 structure and physiological function α-and β-subunit, 370, 373–374 domain III and IV, 373 fast and slow inactivation modes, 372–373 intracellular binding site, 373 Nav1.5 expression, 370 SS1–SS2 region, 371–372 tetrodotoxin (TTX) and site directed mutagenesis, 371–372 topology, 369f, 371 voltage-gated Na+ channels activation, 372 β-subunits and regulatory protein ankyrins, 385 caveolin-3 (Cav3), 385 cytoskeletal protein SNTA1, 385 GPDL-1, 385 Kir2.1 and Nav1.5 expressions, 386 multicopy suppressor of gspl (MOG1), 385 sudden infant death syndrome (SIDS), 384 Castration-resistant prostate cancer (CRPC) androgen receptor (AR) regulation and function, 330–331 413 androgen receptor splice variants (AR-Vs), 342 clinical significance, 346 coregulators interaction, 349 IL-6, 337 whole-exome sequence analysis, 340 CCR5 chemokine receptor and HIV infection blocking drugs, 246–247 effects of, 219–220 immune reconstitution inflammatory syndrome, 247–248 in inflammatory disease, 218–219 maraviroc (MVC), 246 physiological consequences active mutant, 239–240 AIDS pathogenesis, 236–237 anti-CCR5 receptor antibodies, 243–244 coreceptor signaling, 235–236 distinct receptor conformations, 237–238 inactive conformations, 241–242 nonfunctional CCR5-Δ32 allele, 242 N-terminus residues, 242–243 posttranslational receptor modifications, 237–238 receptor density, 236 signaling activity, 237–238 small-molecule antagonists, 244–245 T cells and macrophages, 235–236 physiological functions, 217–218 wild-type receptor β-arrestin recruitment, role of, 226–227 cytoskeleton and chemotaxis, 225–226 Gi protein activation, 223 G protein signaling pathways, 228 Gq/11, role of, 223–224 HIV Env-and gp120-stimulate signaling, 228–235 membrane raft location, 221–223 tyrosine kinases activation, 224–225 Chemokine CXC receptors CXCR1 clinical significance, 271–272 constitutively active mutation (V6.40A and V6.40N), 273–275 414 Chemokine CXC receptors (Continued ) structural features and regulation, 272–273 CXCR2 clinical significance, 275 constitutively active mutation (D138V), 276–277 regulation of, 275–276 CXCR3 clinical significance, 277–278 constitutively active mutation (N3.35A, N3.35S, and T2.56P), 278–279 structural features and regulation, 278 CXCR4 clinical significance, 279–280 constitutively active mutation (N119S and N119A), 282–283 structural features and regulation, 280–282 CXCR5, 283–284 CXCR6, 284–285 CXCR7 clinical significance, 285–286 CXCR4/CXCR7 heterodimer and biased arrestin signaling, 287–288 G protein-coupled receptor (GPCR) signaling pathways constitutively active chemokine receptor mutants, 269, 271t disease and expression in immune cells, 269, 270t 3D structure, 269 hydrophobic core and cytoplasmic domains, 267–268 ionic lock, 267–268 ligands, 267 receptor conformations, 267 seven-transmembrane domain structure, 267 Kaposi’s sarcoma-associated herpesvirus G protein-coupledreceptor (KSHVGPCR) clinical significance, 288 constitutively active mutation, 290–291 structural features and regulation, 288–290 Index Clozapine, 177, 181f Conformational selection theory, 122 Congenital night blindness (CNB), 6t G90D mutation, 15–17 T94I, A292E, and A295V mutations, 17–19 Constitutively active mutants (CAMs) angiotensin II type (AT1) receptor (see Angiotensin II type (AT1) receptor) bitter taste receptors (T2Rs) antagonists and inverse agonists, 318–319 calcium mobilization assay, 313 competition dose–response assays, 318 definition, 311–312 D/ERY motif, 312 downstream cellular signal, 318–319 experimental methods and detection systems, 318–319 hyperresponsive/hyporesponsive types, 312, 312f inositol triphosphate (IP3) assay, 314–315 intracellular loop (ICL3), 316–318 molecular modeling, 315 normoresponsive/nonmoresponsive types, 312, 312f δ opioid and β2-adrenergic receptors (ADRB2), 311–312 receptor density effect, 313–314, 314f transmembrane (TM) domain, 315–316 follicle-stimulating hormone receptor (FSHR) amino acid sequence homology, 39–40 antagonists, 65–66 β-arrestins, 40–41 basal activity, 62–63 ERK1/2 MAPK signaling pathway, 40–41 Gαs/cAMP/PKA signaling pathway, 40–41 G protein subtypes, 40–41 in humans, 46–50, 47f, 49f, 308t hydrophilic residue Ser273, 62 ionic lock, 63–65 in mice model, 55–59, 57f 415 Index negative allosteric modulator, 66 promiscuous activation, 62–63 residues and structural elements, 63, 64f Ser28, substitution of, 62 luteinizing hormone–choriogonadotropin receptor (LHCGR) amino acid sequence homology, 39–40 basal activity, 62–63 deglycosylated luteinizing hormone (LH), 67 Gαs/cAMP/PKA signaling pathway, 40–41 glycopeptides and oligosaccharides, 67–68 G protein subtypes, 40–41 in humans, 41–46, 43f, 308t mice model, 51–55, 52f Ser277, hydrophobic residue, 62 small molecule antagonists, 66–67 TMD3–TMD6 ionic lock, 63–65 Cytokines, 337–338 CRPC See Castration-resistant prostate cancer (CRPC) D Dopamine receptors antipsychotic drugs, 177, 180t clozapine, 177, 181f D1-class receptor β2-adrenoceptors (β2AR), 182 desensitization, 196–197 extracellular loop (ECL3), 185–186 homology model, 186–188 internalization, 196–197 lipid rafts, 195–196 maximal binding capacity (Bmax) value, 184–185 pharmacological characteristics, 177–180 protein kinase C (PKC), 194–195 structural determinants, 182 terminal receptor locus (TRL) domain, 178f, 183, 184f three-dimensional crystallographic study, 185 transmembrane (TM) domain, 186 D2-class receptor D2sR, 191 haloperidol, 189 mechanisms, 191–192 NG 108-15 cell, 189–190 pharmacological and clinical properties, 192–193 ternary complex model, 193 hippocampal function, 199–200 Huntington’s disease (HD), 201 hypo-and hyperstimulation, 198 hypothalamic ANF neurons, 199 kidney and hypertension, 200–201 Parkinson’s disease (PD), 202 thioridazine, 180t, 198–199 E Enzalutamide, 351 Extracellular loop (ECL3), 185–186 F Familial male-limited precocious puberty (FMPP), 41–42 Familial testotoxicosis, 41–42 Follicle-stimulating hormone receptor (FSHR) amino acid sequence homology, 39–40 antagonists, 65–66 β-arrestins, 40–41 basal activity, 62–63 ERK1/2 MAPK signaling pathway, 40–41 Gαs/cAMP/PKA signaling pathway, 40–41 G protein subtypes, 40–41 in humans, 46–50, 47f, 49f hydrophilic residue Ser273, 62 ionic lock, 63–65 in mice model, 55–59, 57f negative allosteric modulator, 66 promiscuous activation, 62–63 residues and structural elements, 63, 64f Ser28, substitution of, 62 G Glycerol-3-phosphate dehydrogenase 1-like protein (GPD1L), 385 Glycoprotein hormones, 38–39 Gonadotropin receptor CAMs follicle-stimulating hormone receptor (FSHR) 416 Gonadotropin receptor CAMs (Continued ) amino acid sequence homology, 39–40 antagonists, 65–66 β-arrestins, 40–41 basal activity, 62–63 ERK1/2 MAPK signaling pathway, 40–41 Gαs/cAMP/PKA signaling pathway, 40–41 G protein subtypes, 40–41 in humans, 46–50, 47f, 49f, 308t hydrophilic residue Ser273, 62 ionic lock, 63–65 in mice model, 55–59, 57f negative allosteric modulator, 66 promiscuous activation, 62–63 residues and structural elements, 63, 64f Ser28, substitution of, 62 gain-of-function mutations, 41 luteinizing hormone–choriogonadotropin receptor (LHCGR) amino acid sequence homology, 39–40 basal activity, 62–63 deglycosylated luteinizing hormone (LH), 67 Gαs/cAMP/PKA signaling pathway, 40–41 glycopeptides and oligosaccharides, 67–68 G protein subtypes, 40–41 in humans, 41–46, 43f, 308t mice model, 51–55, 52f Ser277, hydrophobic residue, 62 small molecule antagonists, 66–67 TMD3–TMD6 ionic lock, 63–65 ligand-induced activation, 59–61 loss-of-function mutations, 41 GPCRs See G protein-coupled receptors (GPCRs) G protein-activated inwardly rectifying K+ channel (GIRK) cytoplasmic pore, 403–404 phosphatidylinositol 4,5-bisphosphate (PIP2), 399 G protein-coupled receptors (GPCRs) β2-adrenergic receptor (ADRB2), 136 autoantibody activation, 164–165 Index bitter taste receptors (T2R) (see Bitter taste receptors (T2Rs)) chemokine CXC receptors constitutively active mutants, 269, 271t disease and expression in immune cells, 269, 270t 3D structure, 269 hydrophobic core and cytoplasmic domains, 267–268 ionic lock, 267–268 ligands, 267 receptor conformations, 267 seven-transmembrane domain structure, 267 complex mechanism, 160–161 extended ternary complex model, 136 gain-of-function phenotype, 157 inactive and active receptor, 85–86 melanocortin-4 receptor (MC4R), constitutive activity in (see Melanocortin-4 receptor (MC4R)) mutation-induced constitutive activity, 158–160 δ-opioid receptor, 136 pharmacological intervention, 83, 84f physiological/pathophysiological mechanism, 82–83 rhodopsin (see Rhodopsin) signaling activity, 83–85, 86 stretch activation, 165 wild-type (WT) receptor, 136 Gs-mediated basal signaling activity features, 88, 89f physiological aspects advantages, 93–96 endogenous level, 93 structural determinants extracellular region, 92 follicle-stimulating hormone receptor (FSHR) vs luteinizing hormone–choriogonadotropin receptor (LHCGR), 90 intracellular region, 88–90 ligand-independent activity, 92–93 serpentine domain, 91–92 transmembrane helix (TMH), 89f, 90–91 417 Index H glycopeptides and oligosaccharides, 67–68 G protein subtypes, 40–41 in humans familial testotoxicosis, 41–42 feature, 43–46 gain-of-function mutations, TSHR, 42–43, 43f, 44t mice model, 51–55, 52f Ser277, hydrophobic residue, 62 small molecule antagonists, 66–67 TMD3–TMD6 ionic lock, 63–65 Haloperidol, 189 Human immunodeficiency virus (HIV) infection See CCR5 chemokine receptor and HIV infection Huntington’s disease (HD), 201 Hypersympathetic vasomotor tone model, 168–169 L Leber congenital amaurosis (LCA) apoprotein opsin, 6t, 13–14, 26 early vision loss, 12–13 lecithin retinol acyltransferase (LRAT) and retinal pigment epitheliumspecific 65 kDa protein (RPE65), 12–13 Lecithin retinol acyltransferase (LRAT), 12–13 Lev–Lene´gre syndrome, 383 Long QT syndrome (LQTS) action potential, electrocardiogram (ECG), and currents, 371f diagnosis, 378–379 gain-of-function mechanisms, 377 heterologous expression and electrophysiological measurements, 375–376 hinged-lid model, 376–377 identical intragenic deletions and missense mutations, 374–375 inherited/acquired disorder, 374 multiple peptide segments, 376–377 prolonged QT interval, 374 treatment, 379–380 types, 374 Low-renin hypertension model, 166–168 Luteinizing hormone (LH), 38–39 Luteinizing hormone-choriogonadotropin receptor (LHCGR), CAMs amino acid sequence homology, 39–40 basal activity, 62–63 deglycosylated luteinizing hormone (LH), 67 Gαs/cAMP/PKA signaling pathway, 40–41 M Melanocortin-1 receptor (MC1R), 137, 138 Melanocortin-3 receptor (MC3R), 136–137, 141 Melanocortin-4 receptor (MC4R) cAMP levels, 137–138 extracellular signal-regulated kinase (ERK) 1/2 signaling pathway agouti-related protein (AgRP), 142–144, 143f biased agonist stimulated signaling, 142 F267A and I269A, 142 in vitro experiments, 141–142 in vivo, activation of, 141–142 Ipsen 5i and MCL0020, 142–143, 143f, 144 L140, mutations at, 142 M241A, L250A and I266A, 142 ML00253764, 142–143, 143f, 144 Gs-cAMP signaling pathway agouti-related protein (AgRP), 139 defective basal signaling, 138, 139 D146N mutation, 139 H76R and F280L mutations, 139 human and zebra fish MC3R, 141 Ipsen 5i and MCL0020, 139–140, 140f L250Q mutation, 139 ML00253764, 139–140, 140f P230L mutation, 139 sea bass and zebra fish, 140–141 S127L mutation, 139 inverse agonists, treatment of, 146–147 in vivo relevance of, 144–146 physiological processes, regulation of, 137–138 418 Melanocortin-4 receptor (MC4R) (Continued ) proopiomelanocortin (POMC) neurons, 136–137 Melanocortin-2 receptor accessory protein (MRAP1), 140–141 Multicopy suppressor of gspl (MOG1), 385 N NH2-terminal domain (NTD) nuclear receptor (NRs), 331–333 therapeutic approaches, 353 Night blindness See Congenital night blindness (CNB) Nucleoside diphosphate kinase (NDPK), 397–399 O δ-Opioid receptor, 136 Ovarian hyperstimulation syndrome (OHSS), 46–48 P Parkinson’s disease (PD), 202 Phosphatidylinositol 4,5-bisphosphate (PIP2), 399–401 Progressive cardiac conduction disease (PCCD), 383 Proopiomelanocortin (POMC), 136–137, 140–141, 145–146 Protein kinase activation, 231 R Retinal degeneration congenital night blindness (CNB) G90D mutation, 15–17 T94I, A292E, and A295V mutations, 17–19 Leber congenital amaurosis (LCA) apoprotein opsin, 6t, 13–14, 26 early vision loss, 12–13 lecithin retinol acyltransferase (LRAT) and retinal pigment epitheliumspecific 65 kDa protein (RPE65), 12–13 retinitis pigmentosa (RP), 6t G90V mutation, 20–21 K296E and K296M mutations, 21–22 Index S186W and D190N mutations, 19–20 vitamin A deficiency, 13–14 Retinitis pigmentosa (RP), 6t G90V mutation, 20–21 K296E and K296M mutations, 21–22 S186W and D190N mutations, 19–20 Rhodopsin constitutive activity in active-state conformation, 23–27, 24f congenital night blindness (CNB) (see Congenital night blindness (CNB)) Leber congenital amaurosis (LCA) (see Leber congenital amaurosis (LCA)) phenotypes, 22–23 retinitis pigmentosa (RP) (see Retinitis pigmentosa (RP)) vitamin A deficiency, 13–14 molecular switches in, 11f, 26–27 CWxP motif, 10 D(E)RY motif, 11–12 NPxxY motif, 12 protonated Schiff base, 10 TM3–TM5 hydrogen bond network, 10 phototransduction, 3–10, 4f rod photoreceptor cells, 2–3, 4f structure of, 2, 3f S Sick sinus syndrome, 383 Steroid receptor coactivator (SRC), 338–339 Sudden infant death syndrome (SIDS), 384 T Terminal receptor locus (TRL) domain, 178f, 183, 184f Thioridazine, 180t, 198–199 Third intracellular loop (ICL3), 316–318 Thyroid-stimulating hormone receptor (TSHR), 39–40 constitutive signaling activity activation-sensitive position, 96 basal signaling activity (see Gs-mediated basal signaling activity) constitutive inactivation, 100–101 419 Index effects, 98 gain/loss-of-function phenotype, 87–88, 96–100 Gq pathway activation, 86–87 hormone-binding site, 99 inverse agonistic antibodies, 102–104 proteomic analysis, 98 receptor expression, 99 small-molecule ligands, 101–102 G protein-coupled receptor (GPCR) inactive and active receptor, 85–86 pharmacological intervention, 83, 84f physiological/pathophysiological mechanism, 82–83 signaling activity, 83–85, 86 luteinizing hormone–choriogonadotropin receptor (LHCGR) and folliclestimulating hormone receptor (FSHR), 43, 44t, 304 Thyrotropin receptor See Thyroidstimulating hormone receptor (TSHR) Transient receptor potential channel M5 (TRPM5), 305–306 Transmembrane helices (TMHs), 89f, 90–91 T2Rs See Bitter taste receptors (T2Rs) TSHR See Thyroid-stimulating hormone receptor (TSHR) Type muscarinic acetylcholine receptor (M2 receptor), 395–396 V Vitamin A deficiency, 13–14 ... rhodopsin kinase and the binding of arrestin (blue; dark gray in the print version) The MII state decays to opsin upon release of all-trans retinal from the chromophore-binding pocket Opsin must... vitamin A deficiency LCA and vitamin A deficiency eliminate or reduce the pool of 11-cis retinal in the retina, thereby resulting in the presence of the apoprotein opsin rather than rhodopsin in. .. significant increase in basal activity, presumably by breaking interactions that constrain the wild-type receptor in inactive conformation Numerous studies utilized this strategy to gain insights into