scholarly journals The IgG3 Subclass of β1-adrenergic receptor autoantibody is an endogenous biaser of β1AR signaling

2020 ◽  
Author(s):  
Maradumane L. Mohan ◽  
Yuji Nagatomo ◽  
Sromona D. Mukherjee ◽  
Timothy Engelman ◽  
Rommel Morales ◽  
...  
Keyword(s):  
G Protein ◽  
Hek293 Cells ◽  
Autoimmune Response ◽  
G Protein Coupling ◽  
Erk Activation ◽  
Protein Coupling ◽  
Camp Generation ◽  
Β Blocker ◽  
Pre Treatment ◽  
Igg3 Subclass

ABSTRACTAutoantibodies recognizing human β1ARs generated due to dysregulation in autoimmune response are generally associated with deleterious cardiac outcomes. However, cellular studies show that isolates of β1AR autoantibody from patients differentially modulate β1AR function. β1AR autoantibodies belong to the IgG class of immunoglobulins, however it is not known whether the IgG sub-classes mediate variability in β1AR responses. To determine whether the IgG3 subclass of β1AR autoantibodies uniquely modulate β1AR function, HEK293 cells stably expressing human β1ARs were utilized. Treatment of cells with IgG3(-) serum resulted in significant increase of cAMP compared to IgG3(+) serum. Pre-treatment of cells with IgG3(+) serum impaired dobutamine-mediated Adenylate Cyclase (AC) activity and cAMP generation whereas, it surprisingly increased AC activity and cAMP generation with β-blocker metoprolol. Consistently, purified IgG3(+) β1AR autoantibodies impaired dobutamine-mediated cAMP while elevating metoprolol-mediated AC activity and cAMP. Despite IgG3(+) autoantibodies reducing cAMP response to dobutamine, they mediate significant ERK activation upon dobutamine. IgG3(+) β1AR autoantibodies did not alter β2AR function, reflecting their specificity. The study shows that IgG3(+) β1AR autoantibody impairs agonist-mediated G-protein coupling while preferentially mediating G-protein-independent ERK activation. Furthermore, it uniquely biases β-blocker towards G-protein coupling. This unique biasing capabilities of IgG3(+) β1AR autoantibodies may underlie the beneficial outcomes in patients.

scholarly journals The IgG3 subclass of β1-adrenergic receptor autoantibodies is an endogenous biaser of β1AR signaling

2021 ◽  
Vol 32 (7) ◽  
pp. 622-633
Author(s):  
Maradumane L. Mohan ◽  
Yuji Nagatomo ◽  
Prasenjit Prasad Saha ◽  
Sromona D. Mukherjee ◽  
Timothy Engelman ◽  
...  
Keyword(s):  
Heart Failure ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Human Heart ◽  
Human Heart Failure ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Igg3 Subclass

β1-Adrenergic receptor autoantibodies are associated with deleterious consequences; however, the IgG3 subclass provides beneficial outcomes in human heart failure. IgG3 β1AR autoantibody inhibits G-protein coupling, simultaneously activating ERK through G-protein–independent arrestin-dependent mechanisms.

scholarly journals Ligand recognition, unconventional activation, and G protein coupling of the prostaglandin E2 receptor EP2 subtype

2021 ◽  
Vol 7 (14) ◽  
pp. eabf1268
Author(s):  
Changxiu Qu ◽  
Chunyou Mao ◽  
Peng Xiao ◽  
Qingya Shen ◽  
Ya-Ni Zhong ◽  
...  
Keyword(s):  
G Protein ◽  
Rational Design ◽  
Receptor Activation ◽  
Prostaglandin E ◽  
Toggle Switch ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Ligand Selectivity ◽  
Activation Mechanisms ◽  
Prostaglandin E2 Receptor

Selective modulation of the heterotrimeric G protein α S subunit–coupled prostaglandin E2 (PGE2) receptor EP2 subtype is a promising therapeutic strategy for osteoporosis, ocular hypertension, neurodegenerative diseases, and cardiovascular disorders. Here, we report the cryo–electron microscopy structure of the EP2-Gs complex with its endogenous agonist PGE2 and two synthesized agonists, taprenepag and evatanepag (CP-533536). These structures revealed distinct features of EP2 within the EP receptor family in terms of its unconventional receptor activation and G protein coupling mechanisms, including activation in the absence of a typical W6.48 “toggle switch” and coupling to Gs via helix 8. Moreover, inspection of the agonist-bound EP2 structures uncovered key motifs governing ligand selectivity. Our study provides important knowledge for agonist recognition and activation mechanisms of EP2 and will facilitate the rational design of drugs targeting the PGE2 signaling system.

Functional Domains of the Mouse β3-Adrenoceptor Associated with Differential G Protein Coupling

2005 ◽  
Vol 315 (3) ◽  
pp. 1354-1361 ◽  
Author(s):  
Masaaki Sato ◽  
Dana S. Hutchinson ◽  
Tore Bengtsson ◽  
Anders Floren ◽  
Ülo Langel ◽  
...  
Keyword(s):  
G Protein ◽  
Functional Domains ◽  
G Protein Coupling ◽  
Protein Coupling

scholarly journals Dynamics of receptor/G protein coupling in living cells

2005 ◽  
Vol 24 (23) ◽  
pp. 4106-4114 ◽  
Author(s):  
Peter Hein ◽  
Monika Frank ◽  
Carsten Hoffmann ◽  
Martin J Lohse ◽  
Moritz Bünemann
Keyword(s):  
G Protein ◽  
Living Cells ◽  
G Protein Coupling ◽  
Protein Coupling

Mutant M1 muscarinic receptors with increased agonist affinity and G protein coupling

Life Sciences ◽  
1999 ◽  
Vol 64 (6-7) ◽  
pp. 563
Author(s):  
W.S. Messer ◽  
X.-P. Huang ◽  
P.I. Nagy ◽  
F.E. Williams ◽  
S.M. Peseckis
Keyword(s):  
G Protein ◽  
Muscarinic Receptors ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Agonist Affinity ◽  
M1 Muscarinic ◽  
M1 Muscarinic Receptors

scholarly journals Increased Notch 1 Expression and Attenuated Stimulatory G Protein Coupling to Adenylyl Cyclase in Osteonectin-Null Osteoblasts

Endocrinology ◽  
2007 ◽  
Vol 148 (4) ◽  
pp. 1666-1674 ◽  
Author(s):  
Catherine B. Kessler ◽  
Anne M. Delany
Keyword(s):  
Adenylyl Cyclase ◽  
G Protein ◽  
Cell Fate ◽  
Osteoblastic Cells ◽  
Matricellular Protein ◽  
Wild Type ◽  
Notch 1 ◽  
Matrix Assembly ◽  
G Protein Coupling ◽  
Protein Coupling

Osteonectin, or secreted protein acidic and rich in cysteine, is one of the most abundant noncollagen matrix components in bone. This matricellular protein regulates extracellular matrix assembly and maturation in addition to modulating cell behavior. Mice lacking osteonectin develop severe low-turnover osteopenia, and in vitro studies of osteonectin-null osteoblastic cells showed that osteonectin supports osteoblast formation, maturation, and survival. The present studies demonstrate that osteonectin-null osteoblastic cells have increased expression of Notch 1, a well-documented regulator of cell fate in multiple systems. Furthermore, osteonectin-null cells are more plastic and less committed to osteoblastic differentiation, able to pursue adipogenic differentiation given the appropriate signals. Notch 1 transcripts are down-regulated by inducers of cAMP in both wild-type and osteonectin-null osteoblasts, suggesting that the mutant osteoblasts may have a defect in generation of cAMP in response to stimuli. Indeed, many bone anabolic agents signal through increased cAMP. Wild-type and osteonectin-null osteoblasts generated comparable amounts of cAMP in response to forskolin, a direct stimulator of adenylyl cyclase. However, the ability of osteonectin-null osteoblasts to generate cAMP in response to cholera toxin, a direct stimulator of Gs, was attenuated. These data imply that osteonectin-null osteoblasts have decreased coupling of Gs to adenylyl cyclase. Because osteonectin promotes G protein coupling to an effector, our studies support the concept that low-turnover osteopenia can result from reducing G protein coupled receptor activity.

scholarly journals Intracellular Loop 2 Peptides of the Human 5HT1a Receptor are Differential Activators of Gi

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Brian Hall ◽  
Carley Squires ◽  
Keith K. Parker
Keyword(s):  
G Protein ◽  
Pharmacological Intervention ◽  
Intracellular Camp ◽  
Intracellular Loop ◽  
Peptide Mimics ◽  
G Protein Coupling ◽  
5Ht1a Receptor ◽  
Protein Coupling ◽  
Loop Region ◽  
Loop 2

Peptide mimics of intracellular loop 2 (ic2) of the human 5HT1a receptor have been studied with respect to their ability to inhibit agonist binding via interference with receptor-G-protein coupling. These peptides give shallow concentration-effect relationships. Additionally, these peptides have been studied with respect to their ability to trigger the signal transduction system of this Gi-coupled receptor. Two signaling parameters have been quantified: concentration of intracellular cAMP and changes in incorporation into the G protein of a stable analog of GTP. In both cases, peptide mimics near midloop of ic2 actually show agonist activity with efficacy falling off toward both loop termini near TM 3 and TM 4. Previous results have suggested that the loop region near the TM3/ic2 interface is primarily responsible for receptor-G-protein coupling, while the current result emphasizes the mid-ic2 loop region's ability to activate the G protein following initial coupling. A limited number of peptides from the receptor's TM5/ic3 loop vicinity were also studied regarding agonist inhibition and G-protein activation. These peptides provide additional evidence that the human 5HT1a receptor, TM5/ic3 loop region, is involved in both coupling and activation actions. Overall, these results provide further information about potential pharmacological intervention and drug development with respect to the human 5HT1a receptor/G-protein system. Finally, the structural evidence generated here provides testable models pending crystallization and X-ray analysis of the receptor.

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