The Extracellular Calcium-sensing Receptor Dimerizes through Multiple Types of Intermolecular Interactions

Zhang, Zaixiang; Sun, Suchih; Quinn, Stephen; Brown, Edward M.; Bai, Ming

doi:10.1074/jbc.m005958200

Cited by 128 publications

(87 citation statements)

References 18 publications

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“…Similarly, the gap junction permeability of astrocytes is cooperatively inhibited via ET A and ET B receptors: only the combined application of ET A and ET B receptor-selective antagonists block ET-1 action (20). These experimental data fit well with the now widely accepted view that class A (rhodopsin-like) and class C (GABA B -like) G protein-coupled receptors exist as homo-and/or heterodimers (21)(22)(23)(24)(25). The cooperativity of ET-1 action on both ET A and ET B receptors may be explained by the fact that ET-1 is a bivalent ligand, which binds to the ET A receptor via its cyclic N terminus and to the ET B receptor via its extended C terminus.…”

supporting

confidence: 76%

Ligand-dependent Differences in the Internalization of Endothelin A and Endothelin B Receptor Heterodimers

Gregan

Jürgensen

Papsdorf

et al. 2004

Journal of Biological Chemistry

117

106

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Endothelin-1 (ET-1) is a potent vasoactive peptide that acts on endothelin A (ETEndothelins (ET-1, ET-2, and ET-3) 1 are important regulators in the vascular system. They act via two receptors: the endothelin A (ET A ) and endothelin B (ET B ) receptors (1, 2). Although human ET A and ET B receptors share 59% amino acid sequence identity (exceeding 75% at the cytoplasmic face), both receptor subtypes couple to different G proteins and differ in their ligand-induced internalization and intracellular trafficking. Whereas the ET A receptor stimulates G proteins of the G q/11 and G 12/13 families, the ET B receptor activates mainly G proteins of the G i and G q/11 families (3, 4). Whether ET B receptors also stimulate proteins of the G 12/13 family is still controversial and may depend on expression levels or cell types investigated (5, 6). Upon ligand binding, both receptor subtypes are rapidly desensitized by phosphorylation through the G protein-coupled receptor kinase type 2 (7). Following internalization via caveolae and/or clathrin-coated pits, the ET A receptor is recycled back to the cell surface (8, 9). In contrast, the ET B receptor is exclusively internalized via a clathrin-dependent pathway and transported to late endosomes and lysosomes (9, 10).The ET A receptor is mainly expressed in vascular smooth muscle cells. Its activation elicits a long-lasting contraction via an increase in cytosolic Ca 2ϩ concentrations and activation of Rho proteins (11,12). The ET B receptor is predominantly expressed in endothelial cells and stimulates the release of NO and prostacyclin, thereby causing relaxation of vascular smooth muscle cells (13). In addition, ET A and ET B receptors are co-expressed in numerous cells, e.g. astrocytes, cardiomyocytes, epithelial cells of the choroid plexus and the anterior pituitary, and certain vascular smooth muscle cells (14 -16). In disease states, such as atherosclerosis and hypercholesterolemia, vascular smooth muscle cells co-express ET A and ET B receptors (17). Because atypical ligand binding was observed for cells co-expressing ET A and ET B receptors, e.g. astrocytes, epithelial cells of the anterior pituitary, or vascular smooth muscle cells, it was suggested that the two receptor subtypes form heterodimers (15,16,18). For example, in epithelial cells of the anterior pituitary, ET B receptor-selective ligands such as sarafotoxin 6c, ET-3, and IRL1620 were competitors of 125 I-ET-1 binding only in the presence of the ET A receptor-selective antagonist BQ123 (16). In astrocytes, ET A and ET B receptors cooperatively control ET-1 clearance, because only the combi-

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supporting

confidence: 76%

Ligand-dependent Differences in the Internalization of Endothelin A and Endothelin B Receptor Heterodimers

Gregan

Jürgensen

Papsdorf

et al. 2004

Journal of Biological Chemistry

117

106

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“…tCaR possesses the two conserved cysteine residues, Cys 129 and Cys 131 , that are thought to be responsible for intermolecular disulfide bond formation in receptor dimerization of human CaR (27). These two cysteines are positioned in a protruding region of the bilobed venus flytrap domain model for the CaR ECD monomer, and they are suggested to function as part of the dimer interface (27)(28)(29). Preliminary three-dimensional structure prediction with the protein homology-modeling servers CPHmodels (30) and SWISS-MODEL (31), using the crystal structure of the rat metabotropic glutamate receptor subtype 1 (mGluR1)-free form I (PDB code: 1EWT) as a template, confirmed a similar orientation for these two cysteines in tCaR (3).…”

Section: Resultsmentioning

confidence: 99%

cDNA Cloning and Functional Expression of a Ca2+-sensing Receptor with Truncated C-terminal Tail from the Mozambique Tilapia (Oreochromis mossambicus)

Loretz¹,

Pollina

Hyodo

et al. 2004

Journal of Biological Chemistry

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The complete cDNA sequence of the tilapia extracellular Ca 2؉ -sensing receptor (CaR) was determined. The transcript length of tilapia CaR (tCaR) is 3.4 kbp and encodes a 940-amino acid, 7-transmembrane domain protein that is consistent in its structural features with known mammalian and piscine CaRs. The tCaR extracellular domain includes a characteristic hydrophobic segment, conserved cysteine residues that are implicated in receptor dimerization (Cys 129 and Cys 131 ) and in coupling to the transmembrane domain (nine conserved cysteine residues), and conserved serine residues (Ser 147 and The roles for ionic calcium (Ca 2ϩ ) in physiological functions are many and varied and essential for survival. Ca 2ϩ -dependent cellular processes include hormone secretion (stimulussecretion coupling), excitability and cell motility (excitationcontraction coupling), and neurotransmission (Ca 2ϩ -based action potentials). This critical involvement of Ca 2ϩ in these and other cellular functions is unique among ions. Ca 2ϩ is simultaneously a controlled variable in physiological systems, an extracellular messenger in multicellular organisms, and an intracellular mediator in a variety of effector cells.Unicellular organisms acquire Ca 2ϩ from the external environment; they have little control over the composition of the surrounding medium and thus had to evolve plasma membrane-bound and other cellular mechanisms to realize cellular Ca 2ϩ homeostasis eventually permitting some degree of habitat survival and selection. In multicellular organisms, active regulation by integumentary tissues of the composition of an "extracellular fluid," which bathes all cells, assures a constant internal milieu and contributes to normal Ca 2ϩ -dependent cell functions. In terrestrial vertebrates, Ca 2ϩ homeostasis depends upon appropriate dietary intake, renal output, and osseous storage and mobilization of Ca 2ϩ . These processes are well known and are regulated by parathyroid hormone, calcitonin, and 1,25-dihydroxyvitamin D acting on kidney, intestine, and bone. Activation of the Ca 2ϩ -sensing receptor (CaR) 1 by its natural ligand, extracellular Ca 2ϩ , alters parathyroid hormone and calcitonin secretion and inhibits renal 1-hydroxylase to retard the synthesis of 1,25-dihydroxyvitamin D (1, 2). Ca 2ϩ balance is achieved through regulated calciotropic hormone secretion in response to the extracellular Ca 2ϩ concentration ([Ca 2ϩ ] o ); the secreted hormones, in turn, control the activity of Ca 2ϩ -transporting tissues to bring about alterations in [Ca 2ϩ ] o . Interestingly, in fishes, the calcium homeostatic process involves ion-transporting tissues not represented in other vertebrate classes (viz., the mitochondria-rich "chloride cells" of the gills and skin) and a different panel of hormones (prolactin and somatolactin from the pituitary, and stanniocalcin from the piscine corpuscles of Stannius (3)). Opportunities for cutaneous

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“…Par comparaison, la CE 50 du Ca 2+ vis-à-vis de l'inhibition de la sécrétion de PTH dans des cultures de cellules de parathyroïdes bovines est voisine de 1,3 mM [9], une concentration proche de la concentration physiologique du Ca 2+ ionisé dans le sérum [1]. Les courbes d'activation par les ions Ca 2+ indiquent une coopérativité très élevée, qui pourrait s'expliquer par la présence de plusieurs sites de liaison [4] des ions Ca 2+ sur le CaR [10], ou encore par la dimérisation de deux monomères [11]. Ces données expérimentales sont en accord avec l'un des rôles physiologiques de ce récepteur, le contrôle extrêmement précis de l'homéostasie calcique.…”

Section: Structure Et Fonction Du Carunclassified

Comment moduler l’activité du récepteur du calcium extracellulaire ?

Ruat

Pétrel

2004

Med Sci (Paris)

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La régulation de l'homéostasie calcique dans les milieux extracellulaires est un mécanisme vital pour l'organisme, et de nombreuses fonctions physiologiques sont extrêmement sensibles aux variations de la concentration extracellulaire de Ca 2+ (Ca 2+ ec ). L'existence d'un système de régulation de la glande parathyroïde est connue depuis très longtemps. En effet, la sécrétion de la parathormone (PTH), une hormone calciotrope, est contrôlée par les ions Ca 2+ présents dans le sérum [1] (Figure 1). La caractérisation moléculaire du mécanisme de détection des variations de Ca 2+ à partir de glandes parathyroïdes bovines a permis, en 1993, d'isoler un nouveau membre atypique de la famille de récepteurs couplés aux protéines G, le récepteur des ions Ca 2+ extracellulaires (CaR) [2]. Ce récepteur est exprimé par les cellules principales et les cellules C des glandes parathyroïdes et thyroïde, respectivement, où son activation inhibe la sécrétion de PTH et stimule la sécrétion de calcitonine. Dans le rein, le CaR est exprimé sur la membrane basolatérale de la partie corticale ascendante de l'anse de Henlé et, à un niveau plus faible, dans d'autres régions, dont la partie médullaire. Il participerait, au niveau péritubulaire, à l'inhibition exercée par les ions Ca 2+ et Mg 2+ sur leur réabsorption [1]. La présence du CaR au niveau des terminaisons nerveuses innervant les artères cérébrales, ainsi que sur des sous-populations de neurones sensitifs, suggère qu'il pourrait être impliqué dans le contrôle du tonus vasculaire et de la douleur [1,3]. Si la présence du CaR a été identifiée dans diffé-rents tissus tels que l'estomac, le pancréas, le poumon, l'os ou encore la peau, l'identité du type cellulaire exprimant ce récepteur, ainsi que son rôle fonctionnel, ne sont pas encore clairement établis. Structure et fonction du CaRLes récepteurs couplés aux protéines G (RCPG) constituent une vaste famille de protéines membranaires caractérisées par un domaine constitué de sept hélices > Le récepteur du Ca 2+ extracellulaire (CaR), localisé à la membrane de la cellule parathyroï-dienne, répond aux fluctuations des ions Ca 2+ sériques et contrôle l'homéostasie calcique. Il appartient à la classe III des récepteurs couplés aux protéines G. Son activité est contrôlée par divers ions divalents et trivalents, mais aussi par des molécules endogènes telles que les acides aminés aromatiques de forme L ou la spermine. Le développement de molécules calcimimétiques capables de potentialiser les actions du Ca 2+ sur le CaR et de réduire la concentration de la parathormone circulante in vivo, ainsi que des études cliniques récentes, suggèrent qu'il constitue une nouvelle cible thérapeutique pour le traitement des hyperparathyroïdies primaires et secondaires. Les calcilytiques bloquent le CaR et stimulent la sécrétion de parathormone. Ces nouvelles molécules, qui agissent au niveau des sept domaines transmembranaires du CaR, devraient permettre de caractériser les fonctions physiologiques associées au CaR et aux ions Ca 2+ extracellulaires da...

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The Extracellular Calcium-sensing Receptor Dimerizes through Multiple Types of Intermolecular Interactions

Abstract: The extracellular calcium ([Ca 2ϩ ] o )-sensing receptor (CaR) 1 is a G protein-coupled receptor that plays a key role in mineral ion homeostasis by sensing small perturbations in the level of [Ca 2ϩ ] o and modulating the functions of parathyroid and kidney so as to restore [Ca 2ϩ

Cited by 128 publications

References 18 publications

Ligand-dependent Differences in the Internalization of Endothelin A and Endothelin B Receptor Heterodimers

Ligand-dependent Differences in the Internalization of Endothelin A and Endothelin B Receptor Heterodimers

cDNA Cloning and Functional Expression of a Ca2+-sensing Receptor with Truncated C-terminal Tail from the Mozambique Tilapia (Oreochromis mossambicus)

Comment moduler l’activité du récepteur du calcium extracellulaire ?

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