Role of the conserved NPxxY motif of the 5-HT2A receptor in determining selective interaction with isoforms of ADP-Ribosylation Factor (ARF)

Johnson, Mark; Robertson, Derek N.; Holland, Pamela J.; Lutz, Eve M.; Mitchell, Rory

doi:10.1016/j.cellsig.2006.02.002

Cited by 27 publications

(33 citation statements)

References 38 publications

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Section: Other Proteins Interacting With 5-htr C-terminimentioning

confidence: 98%

“…ARF proteins bind to a conserved NPxxY motif that has been found in a number of rhodopsin family GPCRs and that is located at the junction of the transmembrane domain 7 and the C-terminal domain (Johnson et al 2006). This motif is critical in determining selective interaction with isoforms of ARF (Johnson et al 2006). The interaction between 5-HT 2A R and ARF proteins appears to be essential for 5-HT 2A R-mediated PLD activation, which is independent of Gα q/11 (Robertson et al 2003).…”

Section: Other Proteins Interacting With 5-htr C-terminimentioning

confidence: 98%

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Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation

et al. 2006

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Serotonin (5-hydroxytryptamine, 5-HT) is, without doubt, the neurotransmitter for which the number of receptors is the highest. Fifteen genes encoding functional 5-HT receptors have been cloned in mammalian brain. 5-HT(3) receptors are ionotropic receptors, whereas all the others are metabotropic G-protein-coupled receptors (GPCRs). 5-HT receptor diversity is further increased by post-genomic modifications, such as alternative splicing (up to 10 splice variants for the 5-HT(4) receptor) or by mRNA editing in the case of 5-HT(2C) receptors. The cellular and behavioral implications of 5-HT(2C) receptor editing are of great physiological importance. Signaling of 5-HT receptors involves a great variety of pathways, but only some of these have been demonstrated in neurons. The classical view of neurotransmitter receptors localized within the synaptic cleft cannot be applied to 5-HT receptors, which are mostly (but not exclusively) localized at extra-synaptic locations either pre- or post-synaptically. 5-HT receptors are engaged in pre- or post-synaptic complexes composed of many GPCR-interacting proteins. The functions of these proteins are starting to be revealed. These proteins have been implicated in targeting, trafficking to or from the membrane, desensitization, and fine-tuning of signaling.

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Section: Other Proteins Interacting With 5-htr C-terminimentioning

confidence: 98%

Section: Other Proteins Interacting With 5-htr C-terminimentioning

confidence: 98%

Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation

et al. 2006

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“…Previous studies reported that a N376 to D mutation in the conserved NPxxY motif of the 5-HT 2A receptor alters the coupling preference from ARF1 to ARF6 [14,41]. These data suggest that the presence of the N or a D in this highly conserved motif is an important, but not exclusive, determinant of which ARF isoform interacts with the GPCR, since some NPxxY motif-containing receptors such as the M 3 R used both isoforms.…”

Section: Discussionmentioning

confidence: 66%

“…P 2U purinergic receptor, PAR, GnRH receptor, etc.) [42], a fact that seems to confer a different pattern of small G proteins activation [14]. Collectively, our results suggest that NPxxY→DPxxY swapping in the M 3 R it switch the receptor from one signaling complex (e.g.…”

mentioning

confidence: 71%

“…Interestingly, by means of mutagenesis and molecular modeling studies based on the rhodopsin crystal structure it has been shown that this motif is involved in an interaction network that modulates receptor's expression, signaling and trafficking [10][11][12][13][14]. Also, based on computational studies a theoretical model that explains the special structural features of the conserved N/DP motif has been proposed.…”

Section: Introductionmentioning

confidence: 99%

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Dissecting the Conserved NPxxY Motif of the M<sub>3</sub> Muscarinic Acetylcholine Receptor: Critical Role of Asp-7.49 for Receptor Signaling and Multiprotein Complex Formation

Borroto-Escuela

Romero-Fernández²,

Correia³

et al. 2011

Cell Physiol Biochem

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Acetylcholine challenge produces M₃ muscarinic acetylcholine receptor activation and accessory/scaffold proteins recruitment into a signalsome complex. The dynamics of such a complex is not well understood but a conserved NPxxY motif located within transmembrane 7 and juxtamembrane helix 8 of the receptor was found to modulate G protein activation. Here by means of receptor mutagenesis we unravel the role of the conserved M₃ muscarinic acetylcholine receptor NPxxY motif on ligand binding, signaling and multiprotein complex formation. Interestingly, while a N7.49D receptor mutant showed normal ligand binding properties a N7.49A mutant had reduced antagonist binding and increased affinity for carbachol. Also, besides this last mutant was able to physically couple to Gα_q/11 after carbachol challenge it was neither capable to activate phospholipase C nor phospholipase D. On the other hand, we demonstrated that the Asn-7.49 is important for the interaction between M₃R and ARF1 and also for the formation of the ARF/Rho/β γ signaling complex, a complex that might determine the rapid activation and desensitization of PLD. Overall, these results indicate that the NPxxY motif of the M₃ muscarinic acetylcholine receptor acts as key conformational switch for receptor signaling and multiprotein complex formation.

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Small GTPases and Their Role in Regulating G Protein-Coupled Receptor Signal Transduction

Ribeiro

Ferguson

2009

Signal Transduction: Pathways, Mechanisms and Diseases

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Role of the conserved NPxxY motif of the 5-HT2A receptor in determining selective interaction with isoforms of ADP-Ribosylation Factor (ARF)

Cited by 27 publications

References 38 publications

Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation

Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation

Dissecting the Conserved NPxxY Motif of the M<sub>3</sub> Muscarinic Acetylcholine Receptor: Critical Role of Asp-7.49 for Receptor Signaling and Multiprotein Complex Formation

Small GTPases and Their Role in Regulating G Protein-Coupled Receptor Signal Transduction

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