Members of RTP and REEP Gene Families Influence Functional Bitter Taste Receptor Expression

Behrens, Maik; Bartelt, Juliane; Reichling, Claudia; Winnig, Marcel; Kühn, Christina; Meyerhof, Wolfgang

doi:10.1074/jbc.m513637200

Cited by 126 publications

(148 citation statements)

References 34 publications

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“…However, for humans, only nine hTAS2Rs are analyzed for function and five hTAS2R genes for gustatory expression, respectively Bufe et al, 2002Bufe et al, , 2005Behrens et al, 2004;Kuhn et al, 2004;Pronin et al, 2004), leaving the majority of hTAS2Rs uncharacterized. Reports on the extragustatory expression of TAS2R genes in respiratory epithelia (Finger et al, 2003), gastrointestinal tissues and cells derived thereof (Wu et al, 2002(Wu et al, , 2005, and testes (Matsunami et al, 2000;Behrens et al, 2006) indicate additional nongustatory functions for TAS2Rs, making it necessary to confirm for every single TAS2R its potential role in taste sensation.…”

Section: Discussionmentioning

confidence: 99%

Gustatory Expression Pattern of the Human TAS2R Bitter Receptor Gene Family Reveals a Heterogenous Population of Bitter Responsive Taste Receptor Cells

Behrens¹,

Foerster²,

Staehler³

et al. 2007

J. Neurosci.

195

147

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Section: Discussionmentioning

confidence: 99%

Gustatory Expression Pattern of the Human TAS2R Bitter Receptor Gene Family Reveals a Heterogenous Population of Bitter Responsive Taste Receptor Cells

Behrens¹,

Foerster²,

Staehler³

et al. 2007

J. Neurosci.

195

147

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“…There is a perfect correlation between the ability of different MRAP mutants and MRAP2 to disrupt MC5 receptor dimerization and to prevent receptor trafficking to the plasma membrane. Interestingly, heterodimerization of and ␦ opioid receptors is promoted by RTP4 (25), a member of the RTP family of accessory proteins that facilitate odorant and taste receptor expression (26,27).…”

Section: Discussionmentioning

confidence: 99%

Opposite Effects of the Melanocortin-2 (MC2) Receptor Accessory Protein MRAP on MC2 and MC5 Receptor Dimerization and Trafficking

Sebag

Hinkle

2009

Journal of Biological Chemistry

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MC2 (ACTH) receptors require MC2 receptor accessory protein (MRAP) to reach the cell surface. In this study, we show that MRAP has the opposite effect on the closely related MC5 receptor. In enzyme-linked immunosorbent assay and microscopy experiments, MC2 receptor was retained in the endoplasmic reticulum in the absence of MRAP and targeted to the plasma membrane with MRAP. MC5 receptor was at the plasma membrane in the absence of MRAP, but trapped intracellularly when expressed with MRAP. Using bimolecular fluorescence complementation, where one fragment of yellow fluorescent protein (YFP) was fused to receptors and another to MRAP, we showed that MC2 receptor-MRAP dimers were present at the plasma membrane, whereas MC5 receptor-MRAP dimers were intracellular. Both MC2 and MC5 receptors co-precipitated with MRAP. MRAP did not alter expression of ␤2-adrenergic receptors or co-precipitate with them. To determine if MRAP affects formation of receptor oligomers, we co-expressed MC2 receptors fused to YFP fragments in the presence or absence of MRAP. YFP fluorescence, reporting MC2 receptor homodimers, was readily detectable with or without MRAP. In contrast, MC5 receptor homodimers were visible in the absence of MRAP, but little fluorescence was observed by microscopic analysis when MRAP was co-expressed. Co-precipitation of differentially tagged receptors confirmed that MRAP blocks MC5 receptor dimerization. The regions of MRAP required for its effects on MC2 and MC5 receptors differed. These results establish that MRAP forms stable complexes with two different melanocortin receptors, facilitating surface expression of MC2 receptor but disrupting dimerization and surface localization of MC5 receptor.In mammals, the five members of the melanocortin (MC 2 ) receptor family play diverse physiological roles. MC1 receptors (melanocyte-stimulating hormone receptors) control pigmentation in many animals, MC2 receptors (ACTH receptors) regulate adrenal corticosteroid synthesis, MC3 and MC4 receptors in brain influence food intake and energy expenditure, and MC5 receptors control exocrine gland secretion (1). Melanocortin receptors (MC1 through MC5) are structurally related G protein-coupled receptors that respond to agonists with an increase in cAMP. The receptors differ in their affinity for physiological agonists (␣-, ␤-, and ␥-melanocyte-stimulating hormone and ACTH) and antagonists (agouti and agouti-related protein).Unlike other melanocortin receptors, MC2 receptors are selectively regulated by ACTH. The MC2 receptor is also unusual in its requirement for an accessory protein, the MC2 receptor accessory protein (MRAP) (2). MRAP must be expressed with the MC2 receptor in order for the receptor to undergo glycosylation, traffic to the plasma membrane, bind ACTH, and stimulate adenylyl cyclase (2-4). Individuals with inactivating mutations of either the MC2 receptor or MRAP suffer from ACTH resistance and severe glucocorticoid deficiency (2).MRAP is a small protein with a conserved amino terminus, single membrane-spann...

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“…Site-directed mutagenesis of hTAS2R cDNAs was done by PCR-mediated recombination (33), as described previously (34). For a list of oligonucleotides, see Table S3.…”

Section: Methodsmentioning

confidence: 99%

Structural requirements of bitter taste receptor activation

Brockhoff

Behrens²,

Niv³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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158

183

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An important question in taste research is how 25 receptors of the human TAS2R family detect thousands of structurally diverse compounds. An answer to this question may arise from the observation that TAS2Rs in general are broadly tuned to interact with numerous substances. Ultimately, interaction with chemically diverse agonists requires architectures of binding pockets tailored to combine flexibility with selectivity. The present study determines the structure of hTAS2R binding pockets. We focused on a subfamily of closely related hTAS2Rs exhibiting pronounced amino acid sequence identities but unique agonist activation spectra. The generation of chimeric and mutant receptors followed by calcium imaging analyses identified receptor regions and amino acid residues critical for activation of hTAS2R46, -R43, and -R31. We found that the carboxyl-terminal regions of the investigated receptors are crucial for agonist selectivity. Intriguingly, exchanging two residues located in transmembrane domain seven between hTAS2R46, activated by strychnine, and hTAS2R31, activated by aristolochic acid, was sufficient to invert agonist selectivity. Further mutagenesis revealed additional positions involved in agonist interaction. The transfer of functionally relevant amino acids identified in hTAS2R46 to the corresponding positions of hTAS2R43 and -R31 resulted in pharmacological properties indistinguishable from the parental hTAS2R46. In silico modeling of hTAS2R46 allowed us to visualize the putative mode of interaction between agonists and hTAS2Rs. Detailed structure-function analyses of hTAS2Rs may ultimately pave the way for the development of specific antagonists urgently needed for more sophisticated analyses of human bitter taste perception.calcium imaging | G protein-coupled receptors | hTAS2R

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Members of RTP and REEP Gene Families Influence Functional Bitter Taste Receptor Expression

Cited by 126 publications

References 34 publications

Gustatory Expression Pattern of the Human TAS2R Bitter Receptor Gene Family Reveals a Heterogenous Population of Bitter Responsive Taste Receptor Cells

Gustatory Expression Pattern of the Human TAS2R Bitter Receptor Gene Family Reveals a Heterogenous Population of Bitter Responsive Taste Receptor Cells

Opposite Effects of the Melanocortin-2 (MC2) Receptor Accessory Protein MRAP on MC2 and MC5 Receptor Dimerization and Trafficking

Structural requirements of bitter taste receptor activation

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