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Complete Dissertation VU Research Portal Signal transduction of the histamine H3 receptor Bongers, G.M. 2008 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Bongers, G. M. (2008). Signal transduction of the histamine H3 receptor. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 05. Oct. 2021 16 December 2008 om 10.45u Aula van de Vrije Universiteit, De Boelelaan 1105 te Amsterdam Uitnodiging Voor de promotie van Gerold Bongers Na afloop is er een receptie [email protected] receptor 3 of the G.M. Bongers Signal transduction histamine H Signal transduction of the histamine H3 receptor G.M. Bongers 2008 Signal transduction of the histamine H3 receptor Gerold Bongers The research described in this thesis was performed at the Leiden/Amsterdam Center for Drug Research, Faculty of Exact Sciences, Division of Medicinal Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands. The research of the author was supported in part by Abbott Laboratories, Illinois, United States. ISBN 978-90-9023745-9 VRIJE UNIVERSITEIT Signal transduction of the histamine H3 receptor ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op geZag van de rector magnificus prof.dr. L.M. Bouter, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de faculteit der Exacte Wetenschappen op dinsdag 16 december 2008 om 10.45 uur in de aula van de universiteit, De Boelelaan 1105 door Gerardus Martinus Bongers geboren te Oss promotor: prof.dr. R. Leurs copromotor: dr. R.A. Bakker Table of Contents Chapter 1 7 Introduction 7 Chapter 2 33 Molecular aspects of the histamine H3 receptor 33 Chapter 3 51 Constitutive activity of histamine H3 receptors stably expressed in SK- N-MC Cells: display of agonism and inverse agonism by H3 antagonists 51 Chapter 4 67 A 80 amino acid deletion in the third intracellular loop of a naturally occurring human histamine H3 isoform confers pharmacological differences and constitutive activity 67 Chapter 5 91 G-protein coupling of human histamine H3 receptor isoforms 91 Chapter 6 109 The Akt/GSK-3! axis as a new signaling pathway of the histamine H3 receptor 109 Chapter 7 129 Histamine H3 receptor-mediated release of intracellular calcium via a Gi/o-phospholipase C dependent mechanism 129 Chapter 8 139 Discussion and conclusions 139 Samenvatting 150 References 153 Curriculum Vitae 170 List of publications 171 List of abbreviations 172 Chapter 1 Introduction 7 Chapter 1 G-protein coupled receptors G-protein coupled receptors (GPCRs) are a large family of membrane-bound proteins that convert diverse stimuli like odors, photons, neurotransmitters, hormones, peptides and proteases, via guanine nucleotide-binding proteins (G- proteins) into intracellular responses. GPCRs are characteriZed by seven alpha helical transmembrane (TM) domains and are found in eukaryotes, including yeast, plants, choanoflagellates, and animals. They are involved in numerous physiological processes like smell, taste, vision, behavior and mood, regulation of the immune system and autonomic nervous system transmission. GPCRs are considered as an attractive drug target by the pharmaceutical industry, because GPCRs are involved in the regulation of almost every major mammalian physiological process and are readily accessible to drugs due to their localization on the cell surface. In fact, 30% of all drugs on the market are targeting GPCRs, among these are several block-buster drugs like clopidogrel (Plavix®), Fexofenadine hydrochloride (Allegra®), quetiapine (Seroquel®) and metoprolol (Lopressor® or Seloken® (Wise et al., 2002; Service, 2004). Structural features of GPCRs Based on phylogenetic analysis according to the GRAFS classification system GPCRs can be divided into five main classes: the glutamate, rhodopsin, adhesion, frizzled/taste2 and secretin (Figure 1) (Fredriksson et al., 2003). 8 Introduction Figure 1. Phylogenetic relationships between the GPCRs in the human genome, for the rhodopsin family see Figure 2. Adapted from (Fredriksson et al., 2003). The rhodopsin-class of GPCRs is the largest class and can be further divided into four main groups, ", !, # and $ with 13 sub-branches (Figure 2). The rhodopsin class represents receptors like the olfactory receptors ($-group), chemokine receptors (#-group), peptide receptors (!-group) and the biogenic amine receptors ("-group), and is characteriZed by some highly conserved motifs like the (D/E)R(Y/F) motif at the end of TM3 and the NSxxNPxxY motif in TM7. 9 Chapter 1 Figure 2. The phylogenetic relationships between GPCRs in the human rhodopsin family. The rhodopsin family of GPCR can be subdived into four main groups namely: ", !, # and $ with 13 sub-branches. Adapted from (Fredriksson et al., 2003). Structural models of GPCRs are so far mainly based on the crystal structure of bovine rhodopsin (Palczewski et al., 2000). More recently crystal structures became available of the !1-adrenergic receptor and !2-adrenergic receptor (Cherezov et al., 2007; Rasmussen et al., 2007; Rosenbaum et al., 2007; Warne et al., 2008). These crystal structures show that GPCRs consist of a single strand of amino acids with an extracellular N-terminal tail, seven alpha helical domains that traverse the cellular membrane and an intracellular C-terminal tail (Figure 3). Due to its structural features, GPCRs are also know as seven transmembrane receptors, 7TM receptors or heptahelical receptors. 10 Introduction Figure 3. Crystal structure of rhodopsin showing the extracellular loops and the N-terminal tail (bottom), seven alpha helical transmembrane domains (middle), intracellular loops and alpha helical C-terminal tail (top). Adapted from (Palczewski et al., 2000). G-protein dependent signaling The heterotrimeric G-protein consists of a G" subunit and a tight complex formed from a G!-subunit and a G#-subunit. At least 17 G", 5 G! and 14 G#-subunits are know (Wettschureck and Offermanns, 2005), leading to a huge diversity of 1190 theoretical combinations, although not all combinations might be found in vivo. In the basal state the guanine diphosphate (GDP)-bound G"-protein is associated to the !#-complex. Coupling of the heterotrimeric protein to an active receptor promotes the exchange of GDP with guanine triphosphate (GTP) on the G"- subunit and subsequently leading to dissociation of the G"-subunit and !#-complex from the receptor as well as dissociation of the G"-subunit from the !#-complex. The free G"-subunit and !#-complex are now able to modulate a variety of effectors. Termination of the signal is induced by the hydrolysis of GTP by the inherent GTPase activity of the G"-subunit and the subsequent re-association of the GDP-bound G"-subunit with the !#-complex, which can enter a new activation cycle when bound to an activated receptor (Wettschureck and Offermanns, 2005). However, more recently this scheme was shown to be more complex as it has become apparent that dissociation of G-proteins into their subunits is not always essential for their mechanism of action (Klein et al., 2000; Levitzki and Klein, 2002; 11 Chapter 1 Bunemann et al., 2003; Frank et al., 2005). Additionally, various effectors, among which the so-called regulators of G-protein signaling (RGS), accelerate the deactivation of the G-protein mediated signaling by enhancing the GTPase activity on the G"-subunit (Abramow-Newerly et al., 2006b). The G"-subunits can be divided into four main families, the G"s, G"q/11, G"12/13 and G"i/o consisting of various members with different expression patterns (Milligan and Kostenis, 2006). The G"s-proteins are ubiquitously expressed and couples GPCRs to adenylyl cyclase (AC) resulting in an increase in intracellular cAMP levels. The widely expressed G"q-proteins couples receptors to the !-isoforms of phospholipase C (PLC), which catalyses the conversion of phosphatidylinositol 4,5- biphosphate (PIP2) into the second messengers inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), which in turn increase the intracellular calcium 2+ concentration ([Ca ]i) or activate protein kinase C (PKC), respectively. GPCRs that couple to G"q-proteins often activate the ubiquitously expressed G"12/13-proteins as well. The characteriZation of G"12/13-mediated pathways is hampered by the lack of specific inhibitors and promiscuous nature of the GPCRs that couple to these G"-proteins, however, studies have shown G"12/13-proteins activate various + + signaling effectors including phospholipase A2 (PLA2), Na /H -exchanger (NHE) and Rho-guanine nucleotide exchange factor (RhoGEF)-mediated activation of RhoA (Kurose, 2003; Riobo and Manning, 2005). The pertussis toxin (PTX)
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