A Domain for G Protein Coupling in Carboxyl-terminal Tail of Rat Angiotensin II Receptor Type 1A

Sano, Tomoaki; Ohyama, Kenji; Yamano, Yoshiaki; Nakagomi, Yoshiko; Nakazawa, Shinpei; Kikyo, Mitsuhiro; Shirai, Heigoro; Blank, Jonathan S.; Exton, John H.; Inagami, Tadashi

doi:10.1074/jbc.272.38.23631

Cited by 109 publications

(80 citation statements)

References 25 publications

(16 reference statements)

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“…The i3-1 region is located at the amino terminus of the third intracellular (i3) loop of BLT1. Previous reports suggest that the i3 region of several GPCRs functions in G-protein activation (27)(28)(29)(30). In contrast, our findings show that the i3-1 (possibly i3-0) region of BLT1 is specifically required for G i activation.…”

Section: Discussioncontrasting

confidence: 55%

Identification of the Intracellular Region of the Leukotriene B4 Receptor Type 1 That Is Specifically Involved in Gi Activation

Kuniyeda

Okuno

Terawaki

et al. 2007

Journal of Biological Chemistry

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. The i3-1 mutant, with a mutation at the i3 amino terminus, exhibited greatly reduced GTP␥S binding but intact inositol phosphate accumulation triggered by leukotriene B 4 stimulation. These results suggest that the i3-1 region is required only for G i activation. Moreover, in the i3-1 mutant, the deficiency in G i activation was accompanied by a loss of the high affinity leukotriene B 4 binding state seen with the wild type receptor. A three-dimensional model of BLT1 constructed based on the structure of bovine rhodopsin suggests that the i3-1 region may consist of the cytoplasmic end of the transmembrane helix V, which protrudes the helix into the cytoplasm. From mutational studies and three-dimensional modeling, we propose that the extended cytoplasmic helix connected to the transmembrane helix V of BLT1 might be a key region for selective activation of G i proteins.Leukotriene B 4 (LTB 4 ) 3 is an inflammatory lipid mediator biosynthesized from membrane phospholipids by sequential enzymatic reactions (1-4). LTB 4 recruits and activates leukocytes, such as granulocytes, macrophages, monocytes, and T-cells, and plays pivotal roles in host defense and the pathogenesis of inflammatory and immune diseases (5, 6). These actions are mediated by two types of G-protein-coupled receptors (GPCRs). One is the LTB 4 receptor type-1 (BLT1), a high affinity LTB 4 receptor highly expressed in leukocytes (7). The other, BLT2, is a low affinity LTB 4 receptor expressed more ubiquitously than BLT1 in human tissues (8 -11).Many GPCRs can activate more than one G-protein subfamily member. For example, the prostaglandin E 2 receptor EP3D couples to G s and G o (12), platelet-activating factor receptor activates G i and G q (13,14), and the sphingosine 1-phosphate receptors S1P 1 and S1P 2 activate G i and G 12/13 (15). Previous reports suggest that in mediating different cellular events, BLT1 also utilizes different G-proteins, namely pertussis toxin (PTX)-sensitive G i/o and PTX-resistant G q subfamilies of G-proteins (7, 16). Promiscuous G-protein coupling enables GPCRs to mediate diverse signals.The molecular determinants of many receptors participating in G-protein coupling and activation have been investigated. With some exceptions, most of these studies emphasize the role of membrane-proximal regions of the second and third intracellular loops and of the cytoplasmic tail of the receptor (17). However, no consensus sequences for G-protein coupling have been clearly identified.We and others have reported that truncation of its cytoplasmic tail does not impair the ability of BLT1 to activate G-proteins (18,19). To identify regions of BLT1 responsible for G-protein coupling, we performed an extensive mutagenesis study of its intracellular domains. Here, we show that BLT1 distinguishes G i from G 16 at the amino terminus of the third intracellular region (the i3-1 region). Furthermore, Scatchard analyses of the i3-1 mutant revealed that BLT1 requires G i coupling to maintain a high affinity state for LTB 4 . A three-dimen-* Thi...

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Section: Discussioncontrasting

confidence: 55%

Identification of the Intracellular Region of the Leukotriene B4 Receptor Type 1 That Is Specifically Involved in Gi Activation

Kuniyeda

Okuno

Terawaki

et al. 2007

Journal of Biological Chemistry

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“…The recent crystal structures of the human ␤ 2 -adrenergic receptor have an 8th helix underlying the membrane perpendicular to the transmembrane helices which is stabilized by a hydrophobic surface (40 -43). In fact, an 8th helix is thought to be present in most, if not all, rhodopsin-like 7TMRs and play a role in signaling by directly interacting with heterotrimeric G-protein subunits (43)(44)(45)(46)(47)(48)(49), although roles in ligand binding have also been reported (50). The 8th helix of D6 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Multiple Roles for the C-terminal Tail of the Chemokine Scavenger D6

McCulloch¹,

Morrow²,

Milasta

et al. 2008

Journal of Biological Chemistry

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D6 is a heptahelical receptor that suppresses inflammation and tumorigenesis by scavenging extracellular pro-inflammatory CC chemokines. Previous studies suggested this is dependent on constitutive trafficking of stable D6 protein to and from the cell surface via recycling endosomes. By internalizing chemokine each time it transits the cell surface, D6 can, over time, remove large quantities of these inflammatory mediators. We have investigated the role of the conserved 58-amino acid C terminus of human D6, which, unlike the rest of the protein, shows no clear homology to other heptahelical receptors. We show that, in human HEK293 cells, a serine cluster in this region controls the constitutive phosphorylation, high stability, and intracellular trafficking itinerary of the receptor and drives green fluorescent protein-tagged ␤-arrestins to membranes at, and near, the cell surface. Unexpectedly, however, these properties, and the last 44 amino acids of the C terminus, are dispensable for D6 internalization and effective scavenging of the chemokine CCL3. Even in the absence of the last 58 amino acids, D6 still initially internalizes CCL3 but, surprisingly, exposure to ligand inhibits subsequent CCL3 uptake by this mutant. Progressive scavenging is therefore abrogated. We conclude that the heptahelical body of D6 on its own can engage the endocytotic machinery of HEK293 cells but that the C terminus is indispensable for scavenging because it prevents initial chemokine engagement of D6 from inhibiting subsequent chemokine uptake.

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“…Coupling to heterotrimeric G-proteins is dependent upon the proximal region of the carboxyl-terminus of AT1 receptor specifically, the hydrophobic cluster of Tyr312, Phe313 and Leu314 [57], [58]. Site-directed mutagenesis studies have revealed that Tyr312, Phe313 and Leu314 yield receptors that are insensitive to GTPgS and display a reduced capacity to liberate IP3 formation after Ang II stimulation, indicating uncoupling from G-proteins in transfected mammalian cells.…”

Section: Signaling Transduction Pathways Of the At1 Receptormentioning

confidence: 99%

The angiotensin II type 1 receptor and receptor-associated proteins

et al. 2001

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The mechanisms of regulation, activation and signal transduction of the angiotensin II (Ang II) type 1 (AT1) receptor have been studied extensively in the decade after its cloning. The AT1 receptor is a major component of the renin-angiotensin system (RAS). It mediates the classical biological actions of Ang II. Among the structures required for regulation and activation of the receptor, its carboxyl-terminal region plays crucial roles in receptor internalization, desensitization and phosphorylation. The mechanisms involved in heterotrimeric G-protein coupling to the receptor, activation of the downstream signaling pathway by G proteins and the Ang II signal transduction pathways leading to specific cellular responses are discussed. In addition, recent work on the identification and characterization of novel proteins associated with carboxyl-terminus of the AT1 receptor is presented. These novel proteins will advance our understanding of how the receptor is internalized and recycled as they provide molecular mechanisms for the activation and regulation of G-protein-coupled receptors.

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A Domain for G Protein Coupling in Carboxyl-terminal Tail of Rat Angiotensin II Receptor Type 1A

Cited by 109 publications

References 25 publications

Identification of the Intracellular Region of the Leukotriene B4 Receptor Type 1 That Is Specifically Involved in Gi Activation

Identification of the Intracellular Region of the Leukotriene B4 Receptor Type 1 That Is Specifically Involved in Gi Activation

Multiple Roles for the C-terminal Tail of the Chemokine Scavenger D6

The angiotensin II type 1 receptor and receptor-associated proteins

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