Autoantibodies as Endogenous Modulators of GPCR Signaling

The antidiuretic hormone arginine-vasopressin (AVP) forms a signaling complex with the V2 receptor (V2R) and the Gs protein, promoting kidney water reabsorption. Molecular mechanisms underlying activation of this critical G protein–coupled receptor (GPCR) signaling system are still unknown. To fill this gap of knowledge, we report here the cryo–electron microscopy structure of the AVP-V2R-Gs complex. Single-particle analysis revealed the presence of three different states. The two best maps were combined with computational and nuclear magnetic resonance spectroscopy constraints to reconstruct two structures of the ternary complex. These structures differ in AVP and Gs binding modes. They reveal an original receptor-Gs interface in which the Gαs subunit penetrates deep into the active V2R. The structures help to explain how V2R R137H or R137L/C variants can lead to two severe genetic diseases. Our study provides important structural insights into the function of this clinically relevant GPCR signaling complex.

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GPCR Signaling Rides a Wave of Conformational Changes

Cell ◽

10.1016/j.cell.2016.10.006 ◽

2016 ◽

Vol 167 (3) ◽

pp. 602-603 ◽

Cited By ~ 4

Author(s):

Louis M. Luttrell

Keyword(s):

Conformational Changes ◽

Gpcr Signaling

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Poster: CLL-156: Novel CCL22 Mutations Drive Chronic Lymphoproliferative Disorder of NK Cells Through Biased GPCR Signaling

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/s2152-2650(21)01397-5 ◽

2021 ◽

Vol 21 ◽

pp. S222

Author(s):

Shunsuke Kimura ◽

Constance Baer ◽

Mitra S Rana ◽

Andrew Kleist ◽

David J. Feith ◽

...

Keyword(s):

Nk Cells ◽

Lymphoproliferative Disorder ◽

Gpcr Signaling

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Imaging of persistent cAMP signaling by internalized G protein-coupled receptors

Journal of Molecular Endocrinology ◽

10.1677/jme-10-0014 ◽

2010 ◽

Vol 45 (1) ◽

pp. 1-8 ◽

Cited By ~ 47

Author(s):

Davide Calebiro ◽

Viacheslav O Nikolaev ◽

Martin J Lohse

Keyword(s):

G Protein ◽

Intracellular Signaling ◽

Current Model ◽

Living Cells ◽

G Protein Coupled Receptors ◽

Membrane Receptors ◽

Optical Methods ◽

Camp Signaling ◽

Gpcr Signaling ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. They mediate the effects of several endogenous cues and serve as important pharmacological targets. Although many biochemical events involved in GPCR signaling have been characterized in great detail, little is known about their spatiotemporal dynamics in living cells. The recent advent of optical methods based on fluorescent resonance energy transfer allows, for the first time, to directly monitor GPCR signaling in living cells. Utilizing these methods, it has been recently possible to show that the receptors for two protein/peptide hormones, the TSH and the parathyroid hormone, continue signaling to cAMP after their internalization into endosomes. This type of intracellular signaling is persistent and apparently triggers specific cellular outcomes. Here, we review these recent data and explain the optical methods used for such studies. Based on these findings, we propose a revision of the current model of the GPCR–cAMP signaling pathway to accommodate receptor signaling at endosomes.

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Endogenous Modulators of TRP Channels

Current Topics in Medicinal Chemistry ◽

10.2174/1568026611313030014 ◽

2013 ◽

Vol 13 (3) ◽

pp. 398-407 ◽

Cited By ~ 18

Author(s):

Enza Palazzo ◽

Francesco Rossi ◽

Vito de Novellis ◽

Sabatino Maione

Keyword(s):

Trp Channels ◽

Endogenous Modulators

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