Insights into the activation mechanism of the visual receptor rhodopsin

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.

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Mapping the Heart

Microscopy Today ◽

10.1017/s155192951000043x ◽

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.

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

Nature Communications ◽

10.1038/s41467-021-24825-y ◽

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.

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Constitutive Activity among Orphan Class-A G Protein Coupled Receptors

PLoS ONE ◽

10.1371/journal.pone.0138463 ◽

2015 ◽

Vol 10 (9) ◽

pp. e0138463 ◽

Cited By ~ 53

Author(s):

Adam L. Martin ◽

Michael A. Steurer ◽

Robert S. Aronstam

Keyword(s):

G Protein ◽

G Protein Coupled Receptors ◽

Constitutive Activity ◽

Class A ◽

G Protein Coupled

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Applications of molecular replacement to G protein-coupled receptors

Acta Crystallographica Section D Biological Crystallography ◽

10.1107/s090744491301322x ◽

2013 ◽

Vol 69 (11) ◽

pp. 2287-2292 ◽

Cited By ~ 3

Author(s):

Andrew C. Kruse ◽

Aashish Manglik ◽

Brian K. Kobilka ◽

William I. Weis

Keyword(s):

G Protein ◽

Structural Biology ◽

Structural Information ◽

G Protein Coupled Receptors ◽

Integral Membrane Proteins ◽

Molecular Replacement ◽

Gpcr Activation ◽

Health And Disease ◽

Almost All ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are a large class of integral membrane proteins involved in regulating virtually every aspect of human physiology. Despite their profound importance in human health and disease, structural information regarding GPCRs has been extremely limited until recently. With the advent of a variety of new biochemical and crystallographic techniques, the structural biology of GPCRs has advanced rapidly, offering key molecular insights into GPCR activation and signal transduction. To date, almost all GPCR structures have been solved using molecular-replacement techniques. Here, the unique aspects of molecular replacement as applied to individual GPCRs and to signaling complexes of these important proteins are discussed.

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GPCR activation mechanisms across classes and macro/microscales

10.21203/rs.3.rs-354879/v1 ◽

2021 ◽

Author(s):

David Gloriam ◽

Alexander Hauser ◽

Albert Kooistra ◽

Christian Munk ◽

M. Madan Babu

Keyword(s):

Residue Level ◽

G Protein Coupled Receptors ◽

Conformational Selection ◽

Class A ◽

New Methods ◽

Allosteric Communication ◽

Gpcr Activation ◽

Activation Mechanisms ◽

Clinical Drugs ◽

G Protein Coupled

Abstract Two-thirds of human hormones and one-third of clinical drugs activate ~350 G protein-coupled receptors belonging to four classes: A, B1, C and F. Whereas a model of activation has been described for class A, very little is known about the activation of the other classes which differ by being activated by endogenous ligands bound mainly or entirely extracellularly. Here, we show that although they use the same structural scaffold and share several helix macroswitches, the GPCR classes differ in their microswitch residue positions and contacts. We present molecular mechanistic maps of activation for each GPCR class and new methods for contact analysis applicable for any functional determinants. This is the first superfamily residue-level rationale for conformational selection and allosteric communication by ligands and G proteins laying the foundation for receptor-function studies and drugs with the desired modality.

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