Photoinduced receptor confinement drives ligand-independent GPCR signaling

Science ◽  
2021 ◽  
Vol 371 (6536) ◽  
pp. eabb7657
Author(s):  
M. Florencia Sánchez ◽  
Sylvia Els-Heindl ◽  
Annette G. Beck-Sickinger ◽  
Ralph Wieneke ◽  
Robert Tampé
Keyword(s):  
Cell Communication ◽  
Cellular Responses ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Guanine Nucleotide ◽  
Guanine Nucleotide Binding Protein ◽  
Lateral Membrane ◽  
Guanine Nucleotide Binding ◽  
G Protein Coupled

Cell-cell communication relies on the assembly of receptor-ligand complexes at the plasma membrane. The spatiotemporal receptor organization has a pivotal role in evoking cellular responses. We studied the clustering of heterotrimeric guanine nucleotide–binding protein (G protein)–coupled receptors (GPCRs) and established a photoinstructive matrix with ultrasmall lock-and-key interaction pairs to control lateral membrane organization of hormone neuropeptide Y2 receptors in living cells by light. Within seconds, receptor clustering was modulated in size, location, and density. After in situ confinement, changes in cellular morphology, motility, and calcium signaling revealed ligand-independent receptor activation. This approach may enhance the exploration of mechanisms in cell signaling and mechanotransduction.

Mapping the Heart

2010 ◽  
Vol 18 (4) ◽  
pp. 6-8
Author(s):  
Stephen W. Carmichael
Keyword(s):  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
G Protein Coupled Receptors ◽  
Receptor Subtypes ◽  
Cardiac Muscle Cells ◽  
Guanine Nucleotide Binding Protein ◽  
The Common ◽  
Guanine Nucleotide Binding ◽  
First Time ◽  
G Protein Coupled

Some of the receptors on the surface of cardiac muscle cells (cardiomyocytes) mediate the response of these cells to catecholamines by causing the production of the common second messenger cyclic adenosine monophosphate (cAMP). An example of such receptors are the β1- and β2-adrenergic receptors (βARs) that are heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors. Selective stimulation of these two receptor subtypes leads to distinct physiological and pathophysiological responses, but their precise location on the surface of cardiomyocytes has not been correlated with these responses. In an ingenious combination of techniques, Viacheslav Nikolaev, Alexey Moshkov, Alexander Lyon, Michele Miragoli, Pavel Novak, Helen Paur, Martin Lohse, Yuri Korchev, Sian Harding, and Julia Gorelik have mapped the function of these receptors for the first time.

scholarly journals Subcellular redistribution of trimeric G-proteins – potential mechanism of desensitization of hormone response; internalisation, solubilization, down-regulation

2008 ◽  
pp. S1-S10
Author(s):  
Z Drastichová ◽  
L Bouřová ◽  
V Lisý ◽  
L Hejnová ◽  
V Rudajev ◽  
...  
Keyword(s):  
G Proteins ◽  
G Protein Coupled Receptors ◽  
Regulatory Proteins ◽  
Guanine Nucleotide ◽  
Hormone Response ◽  
Ouabain Binding ◽  
Short Summary ◽  
Guanine Nucleotide Binding ◽  
G Protein Coupled ◽  
The Brain

Agonist-induced subcellular redistribution of G-protein coupled receptors (GPCR) and of trimeric guanine-nucleotide binding regulatory proteins (G-proteins) represent mechanisms of desensitization of hormone response, which have been studied in our laboratory since 1989. This review brings a short summary of these results and also presents information about related literature data covering at least small part of research carried out in this area. We have also mentioned sodium plus potassium dependent adenosine triphosphatase (Na, K-ATPase) and 3H-ouabain binding as useful reference standard of plasma membrane purity in the brain.

scholarly journals The Molecular Basis of G Protein–Coupled Receptor Activation

2018 ◽  
Vol 87 (1) ◽  
pp. 897-919 ◽  
Author(s):  
William I. Weis ◽  
Brian K. Kobilka
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Conformational Changes ◽  
Cellular Responses ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Active Conformation ◽  
Allosteric Coupling ◽  
External Stimuli ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) mediate the majority of cellular responses to external stimuli. Upon activation by a ligand, the receptor binds to a partner heterotrimeric G protein and promotes exchange of GTP for GDP, leading to dissociation of the G protein into α and βγ subunits that mediate downstream signals. GPCRs can also activate distinct signaling pathways through arrestins. Active states of GPCRs form by small rearrangements of the ligand-binding, or orthosteric, site that are amplified into larger conformational changes. Molecular understanding of the allosteric coupling between ligand binding and G protein or arrestin interaction is emerging from structures of several GPCRs crystallized in inactive and active states, spectroscopic data, and computer simulations. The coupling is loose, rather than concerted, and agonist binding does not fully stabilize the receptor in an active conformation. Distinct intermediates whose populations are shifted by ligands of different efficacies underlie the complex pharmacology of GPCRs.

scholarly journals Noncanonical scaffolding of Gαi and β-arrestin by G protein–coupled receptors

Science ◽  
2021 ◽  
pp. eaay1833
Author(s):  
Jeffrey S. Smith ◽  
Thomas F. Pack ◽  
Asuka Inoue ◽  
Claudia Lee ◽  
Kevin Zheng ◽  
...  
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Direct Interaction ◽  
Adaptor Proteins ◽  
G Protein Coupled Receptors ◽  
Guanine Nucleotide Binding Protein ◽  
Signaling Mechanism ◽  
Protein Activation ◽  
Guanine Nucleotide Binding ◽  
G Protein Coupled

Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Gα protein subtypes and β-arrestin adaptor proteins. G protein- and β-arrestin-mediated signaling have been considered separable. We show GPCRs promote a direct interaction between Gαi protein subtype family members and β-arrestins, regardless of their canonical Gαi protein subtype coupling. Gαi:β-arrestin complexes bound extracellular signal-regulated kinase (ERK) and their disruption impaired both ERK activation and cell migration, consistent with β-arrestins requiring a functional interaction with Gαi for certain signaling events. These results introduce a GPCR signaling mechanism distinct from canonical G protein activation in which GPCRs cause the formation of Gαi:β-arrestin signaling complexes.

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