scholarly journals Deacetylation as a receptor-regulated direct activation switch for pannexin channels

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yu-Hsin Chiu ◽  
Christopher B. Medina ◽  
Catherine A. Doyle ◽  
Ming Zhou ◽  
Adishesh K. Narahari ◽  
...  
Keyword(s):  
G Protein Coupled Receptors ◽  
Activation Mechanism ◽  
Lysine Acetylation ◽  
Intercellular Signaling ◽  
Histone Deacetylase 6 ◽  
Pannexin 1 ◽  
Lysine Deacetylase ◽  
Channel Opening ◽  
Lysine Residues ◽  
G Protein Coupled

AbstractActivation of Pannexin 1 (PANX1) ion channels causes release of intercellular signaling molecules in a variety of (patho)physiological contexts. PANX1 can be activated by G protein-coupled receptors (GPCRs), including α1-adrenergic receptors (α1-ARs), but how receptor engagement leads to channel opening remains unclear. Here, we show that GPCR-mediated PANX1 activation can occur via channel deacetylation. We find that α1-AR-mediated activation of PANX1 channels requires Gαq but is independent of phospholipase C or intracellular calcium. Instead, α1-AR-mediated PANX1 activation involves RhoA, mammalian diaphanous (mDia)-related formin, and a cytosolic lysine deacetylase activated by mDia – histone deacetylase 6. HDAC6 associates with PANX1 and activates PANX1 channels, even in excised membrane patches, suggesting direct deacetylation of PANX1. Substitution of basally-acetylated intracellular lysine residues identified on PANX1 by mass spectrometry either prevents HDAC6-mediated activation (K140/409Q) or renders the channels constitutively active (K140R). These data define a non-canonical RhoA-mDia-HDAC6 signaling pathway for GαqPCR activation of PANX1 channels and uncover lysine acetylation-deacetylation as an ion channel silencing-activation mechanism.

The Activation Mechanism of Class-III G-Protein Coupled Receptors

2004 ◽  
Vol 13 (1-2) ◽  
pp. 38-51
Author(s):  
J.-P. Pin ◽  
J. Kniazeff ◽  
C. Goudet ◽  
A.-S. Bessis ◽  
P. Rondard ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Activation Mechanism ◽  
Class Iii ◽  
G Protein Coupled

Insights into the activation mechanism of the visual receptor rhodopsin

2012 ◽  
Vol 40 (2) ◽  
pp. 389-393 ◽  
Author(s):  
Steven O. Smith
Keyword(s):  
Structural Biology ◽  
G Protein Coupled Receptors ◽  
Activation Mechanism ◽  
Class A ◽  
Highly Sensitive ◽  
The Common ◽  
Dim Light ◽  
And Function ◽  
G Protein Coupled ◽  
Visual Receptor

Recent advances in the structural biology of GPCRs (G-protein-coupled receptors) have provided insights into their structure and function. Comparisons of the visual and ligand-activated receptors highlight the unique elements of rhodopsin that allow it to function as a highly sensitive dim-light photoreceptor in vertebrates, as well as the common elements that it shares with the large class A GPCR family. However, despite progress, a number of questions remain unanswered about how these receptors are activated.

scholarly journals Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

2015 ◽  
Vol 112 (19) ◽  
pp. 6194-6199 ◽  
Author(s):  
Hannah M. Stoveken ◽  
Alexander G. Hajduczok ◽  
Lei Xu ◽  
Gregory G. Tall
Keyword(s):  
G Protein ◽  
Clinical Utility ◽  
G Protein Coupled Receptors ◽  
Activation Mechanism ◽  
Inhibitory Influence ◽  
Neighboring Cell ◽  
Protein Activation ◽  
G Protein Activation ◽  
G Protein Coupled

The large class of adhesion G protein-coupled receptors (aGPCRs) bind extracellular matrix or neighboring cell-surface ligands to regulate organ and tissue development through an unknown activation mechanism. We examined aGPCR activation using two prototypical aGPCRs, GPR56 and GPR110. Active dissociation of the noncovalently bound GPR56 or GPR110 extracellular domains (ECDs) from the respective seven-transmembrane (7TM) domains relieved an inhibitory influence and permitted both receptors to activate defined G protein subtypes. After ECD displacement, the newly revealed short N-terminal stalk regions of the 7TM domains were found to be essential for G protein activation. Synthetic peptides comprising these stalks potently activated GPR56 or GPR110 in vitro or in cells, demonstrating that the stalks comprise a tethered agonist that was encrypted within the ECD. Establishment of an aGPCR activation mechanism provides a rational platform for the development of aGPCR synthetic modulators that could find clinical utility toward aGPCR-directed disease.

scholarly journals The activation mechanism of class-C G-protein coupled receptors

2004 ◽  
Vol 96 (5) ◽  
pp. 335-342 ◽  
Author(s):  
J.-P Pin ◽  
J Kniazeff ◽  
C Goudet ◽  
A.-S Bessis ◽  
J Liu ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Activation Mechanism ◽  
Class C ◽  
G Protein Coupled

Conserved activation pathways in G-protein-coupled receptors

2012 ◽  
Vol 40 (2) ◽  
pp. 383-388 ◽  
Author(s):  
Xavier Deupi ◽  
Jörg Standfuss ◽  
Gebhard Schertler
Keyword(s):  
G Protein ◽  
Structural Changes ◽  
Transmembrane Helix ◽  
Pharmaceutical Research ◽  
G Protein Coupled Receptors ◽  
Activation Mechanism ◽  
Structural Basis ◽  
Structural Framework ◽  
Activation Pathways ◽  
G Protein Coupled

GPCRs (G-protein-coupled receptors) are seven-transmembrane helix proteins that transduce exogenous and endogenous signals to modulate the activity of downstream effectors inside the cell. Despite the relevance of these proteins in human physiology and pharmaceutical research, we only recently started to understand the structural basis of their activation mechanism. In the period 2008–2011, nine active-like structures of GPCRs were solved. Among them, we have determined the structure of light-activated rhodopsin with all the features of the active metarhodopsin-II, which represents so far the most native-like model of an active GPCR. This structure, together with the structures of other inactive, intermediate and active states of rhodopsin constitutes a unique structural framework on which to understand the conserved aspects of the activation mechanism of GPCRs. This mechanism can be summarized as follows: retinal isomerization triggers a series of local structural changes in the binding site that are amplified into three intramolecular activation pathways through TM (transmembrane helix) 5/TM3, TM6 and TM7/TM2. Sequence analysis strongly suggests that these pathways are conserved in other GPCRs. Differential activation of these pathways by ligands could be translated into the stabilization of different active states of the receptor with specific signalling properties.

The complexity of their activation mechanism opens new possibilities for the modulation of mGlu and GABAB class C G protein-coupled receptors

2011 ◽  
Vol 60 (1) ◽  
pp. 82-92 ◽  
Author(s):  
Philippe Rondard ◽  
Cyril Goudet ◽  
Julie Kniazeff ◽  
Jean-Philippe Pin ◽  
Laurent Prézeau
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Activation Mechanism ◽  
Class C ◽  
G Protein Coupled
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