Deletion of the Serotonin 5-HT2C Receptor PDZ Recognition Motif Prevents Receptor Phosphorylation and Delays Resensitization of Receptor Responses

Backstrom, Jon R.; Price, Raymond D.; Reasoner, Darcie T.; Sanders‐Bush, Elaine

doi:10.1074/jbc.m000922200

Cited by 60 publications

(40 citation statements)

References 25 publications

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“…In the 5-HT 2 receptor family, the distal ct residues are targeted by the PDZ-domain proteins PSD-95 and MUPP-1 (Backstrom et al, 2000;Becamel et al, 2001;Xia et al, 2003), interactions that may modify the signaling function of the receptors. A novel PDZ domain protein, tamalin, has been shown to bind to both mGluR1/5 receptors and the ARF-GEF ARNO (Kitano et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT_2A Receptor

Robertson

Johnson²,

Moggach³

et al. 2003

Mol Pharmacol

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The 5-hydroxytryptamine 2A receptor (5-HT 2A R) is a member of the class I family of rhodopsin-related G protein-coupled receptors. The receptor is known to activate phospholipase C via the heterotrimeric G proteins G q/11 , but we showed previously that it can also signal through the phospholipase D (PLD) pathway in an ADP-ribosylation factor (ARF)-dependent manner that seems to be independent of G q/11 (Mitchell et al., 1998). Both coimmunoprecipitation experiments and the effects of negative mutant ARF constructs on 5-HT 2A R-induced PLD activation here suggested that ARF1 may play a greater role than ARF6 in the function of this receptor. Furthermore, we demonstrated using glutathione S-transferase (GST)-fusion proteins of receptor domains that ARF1 and ARF6 bind to the third intracellular loop (i3) and the carboxy terminal tail (ct) of the 5-HT 2A R. The association of ARF1 with the ct domain of the receptor was stronger than its interaction with i3, or the interactions of ARF6 with either construct. Experiments using ARF mutants that are deficient in GTP loading, and the in vitro addition of GTP␥S suggested that GTP loading enhances ARF1 binding to the receptor. The N376PxxY motif in the transmembrane 7 domain of the receptor (rather than a N376DPxxY mutant form) was shown to be essential for ARF-dependent PLD signaling and ARF1 coimmunoprecipitation. In GST-fusion proteins of the 5-HT 2A R ct domain, mutation of Asn376 to Asp also markedly reduced ARF1-HA binding, although additional motifs in the Asn376 -Asn384 sequence and to a lesser extent elsewhere, seem also to contribute to the interaction.

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Section: Discussionmentioning

confidence: 99%

Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT_2A Receptor

Robertson

Johnson²,

Moggach³

et al. 2003

Mol Pharmacol

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“…The presence of a PDZ-binding motif at the C termini of the 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors has been documented (18,20,48). To date, there are two reports about possible functions of the C-terminal PDZ-binding motifs of the mouse 5-HT 2B (48) and rat 5-HT 2C (49) receptors. The serine at position Ϫ2 was shown to enhance resensitization of the 5-HT 2C receptor responses (49).…”

Section: Discussionmentioning

confidence: 99%

“…To date, there are two reports about possible functions of the C-terminal PDZ-binding motifs of the mouse 5-HT 2B (48) and rat 5-HT 2C (49) receptors. The serine at position Ϫ2 was shown to enhance resensitization of the 5-HT 2C receptor responses (49). This critical Ser Ϫ2 is part of two possible phosphorylation sites contained within the 5-HT 2C receptor PDZ-binding motif.…”

Section: Discussionmentioning

confidence: 99%

Interaction of Serotonin 5-Hydroxytryptamine Type 2C Receptors with PDZ10 of the Multi-PDZ Domain Protein MUPP1

Bécamel¹,

Figge²,

Poliak³

et al. 2001

Journal of Biological Chemistry

157

128

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By using the yeast two-hybrid system, we previously isolated a cDNA clone encoding a novel member of the multivalent PDZ protein family called MUPP1 containing 13 PDZ domains. Here we report that the C terminus of the 5-hydroxytryptamine type 2C (5- There is ample evidence suggesting that the function of a receptor is dependent on its specific subcellular localization. Sequence-specific interactions between proteins provide the basis for the structural and functional organization of receptors within cells. For a few members of the G-protein-coupled receptor family, these interactions have been described to be mediated by C-terminal interactions with PDZ (PSD-95/discs large/ZO-1) domain-containing proteins. The best investigated example is the ␤ 2 -adrenergic receptor, which interacts with the Na ϩ /H ϩ exchanger regulatory factor (NHERF/EBP50) 1 (1). The interaction of NHERF with the ␤ 2 -adrenergic receptor is mediated via binding of the first PDZ domain of NHERF to the extreme C terminus of the ␤ 2 -adrenergic receptor in an agonistdependent manner, thereby regulating Na ϩ /H ϩ exchange (2). NHERF has also been described to link proteins with the actin cytoskeleton through association with ERM (ezrin-radixinmoesin) proteins (3). In fact, the PDZ-mediated interaction of the ␤ 2 -adrenergic receptor with NHERF family proteins has been shown to control recycling of internalized ␤ 2 -adrenergic receptors. Disrupting the ␤ 2 -adrenergic receptor-NHERF interaction perturbs the endocytic sorting of the ␤ 2 -adrenergic receptor, resulting in lysosomal degradation (4).HTC-terminal interactions of G-protein-coupled receptors with PDZ domain-containing proteins extends to a member of the somatostatin receptor family (sst). The subtype sst2 interacts selectively with a highly homologous PDZ domain contained within the protein CortBP1/ProSAP1/Shank2 (5) and the recently cloned synaptic protein SSTRIP (somatostatin receptorinteracting protein)/Spank1/synamon/Shank1 (6). Both proteins belong to a common family recently termed Shanks (7,8) or ProSAP (9), sharing essentially identical domain structures such as ankyrin repeats, an SH3 domain, the PDZ domain, a sterile ␣ motif domain, and a proline-rich region that links Shanks to cortactin, a constituent of the actin cytoskeleton (10).5-HT 2C receptors are broadly expressed in the central nervous system and in the choroid plexus (11,12) and are involved in a diversity of physiological functions such as the control of nociception, motor behavior, endocrine secretion, thermoregulation, modulation of appetite, and the control of exchanges between the central nervous system and the cerebrospinal fluid (13-17). These receptors contain a C-terminal sequence, SSV* (where the asterisk indicates a carboxyl group), corresponding to the T/SXV* motif. This motif is potentially implicated in protein-protein interactions with PDZ domains as originally described for the C termini of the N-methyl-D-aspartate receptor and K ϩ channel subunits (18,19). The T/SXV* motif is also present in C termi...

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“…One could speculate that such a modulating function is required to allow adaptations to both internal and external changes. Two lines of research are being 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 [382]. Thus an inhibition of dephosphorylation would be functionally similar to extracellular receptor activation.…”

Section: Serotonin and Satiety -What Is Next?mentioning

confidence: 99%

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

270

167

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Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 IntroductionWhat are the behavioural and physiological mechanisms that promote satiety? How is satiety defined? Satiety can be seen as a behavioural state which arises from food consumption and suppresses the initiation of eating for a particular period of time [1]. This description alone suggests a high degree of complexity as peripheral post-ingestive and post-absorptive signals need to be relayed to the brain where they are integrated with other signals to produce (or not) the behavioural state called satiety. The state of satiety is brought about a process called satiation, where sensory, cognitive and early post-ingestive mechanisms bring feeding to a halt and thus stopping a meal. Promoting satiation alone must not necessarily lead to reduced total food intake as the frequency of meals could be increased subsequently. Many peripheral and brain mechanisms have been identified that are involved in the expression satiety and it has been suggested that serotonin accelerates satiation and prolongs satiety [2]. In the following, we will review the role of serotonin in satiety in more detail 1 . The reader will see that, despite immense progress made during the last years, the field is still far from being resolved.As serotonin (5-Hydroxytryptamine; 5-HT) is a phylogenetically old neurotransmitter, various functions had time to evolve in different phyla, but maybe also in different species. 5-HT receptors exist in animal cells for millions of years and they are as old as adrenoreceptors ore some peptide receptors, possibly even older [5,6]. Even in invertebrates such as molluscs (Aplysia californica) and annelids (Hirudo medicinalis), 5-HT might functionally be related to food intake [7]. 5-HT is involved in feeding even in the honeybee where it has separate effects in the gut and in the insect brain [8]. In general, however, 5-HT seems rather to be involved in appetitive behaviours in invertebrates whereas it has more of a satiating effect in vertebrates [9]. In general, 5-HT neurons seem to be more extensively distributed throughout the body in lower animals than in higher animals including mammals where 5-HT neurones...

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Deletion of the Serotonin 5-HT2C Receptor PDZ Recognition Motif Prevents Receptor Phosphorylation and Delays Resensitization of Receptor Responses

Cited by 60 publications

References 25 publications

Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT_2A Receptor

Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT_2A Receptor

Interaction of Serotonin 5-Hydroxytryptamine Type 2C Receptors with PDZ10 of the Multi-PDZ Domain Protein MUPP1

Serotonin controlling feeding and satiety

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Deletion of the Serotonin 5-HT2C Receptor PDZ Recognition Motif Prevents Receptor Phosphorylation and Delays Resensitization of Receptor Responses

Cited by 60 publications

References 25 publications

Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT2A Receptor

Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT2A Receptor

Interaction of Serotonin 5-Hydroxytryptamine Type 2C Receptors with PDZ10 of the Multi-PDZ Domain Protein MUPP1

Serotonin controlling feeding and satiety

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Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT_2A Receptor

Selective Interaction of ARF1 with the Carboxy-Terminal Tail Domain of the 5-HT_2A Receptor