G-protein coupled receptor auto-antibodies in thromboangiitis obliterans (Buerger’s disease) and their removal by immunoadsorption

VASA ◽  
2014 ◽  
Vol 43 (5) ◽  
pp. 347-352 ◽  
Author(s):  
Peter F. Klein-Weigel ◽  
Marion Bimmler ◽  
Petra Hempel ◽  
Sebastian Schöpp ◽  
Siegrid Dreusicke ◽  
...  
Keyword(s):  
G Protein ◽  
Adrenergic Receptor ◽  
G Protein Coupled Receptors ◽  
Thromboangiitis Obliterans ◽  
Therapeutic Effects ◽  
Study Group ◽  
Eta Receptor ◽  
Serological Data ◽  
Agonistic Autoantibodies ◽  
G Protein Coupled

Background: Immunhistopathological and serological data favors an immunopathogenesis of thromboangiitis onliterans(TAO, Buerger’s disease). Autoantbodies seem to play a major role. Immunoadsorption (IA) proved to be therapeutically effective. We focused on agonistic autoantibodies (agAAB) directed against G-protein coupled receptors (GPCR) and proved the hypothesis, that these agAAB might be present in TAO and that a five day course of IA might be able to eliminate these agAAB effectively. Patients and methods: Between December 2012 and May 2014 11 TAO-patients were treated by IA in a five day course. AgAAB-analysis was performed using specific ELISA techniques. Results: AgAAB were detected in 9 out of 11 patients (81.8 %).Multiple agAAB were present in 7 patients (63.6 %). A clustering of agAAB directed against loop1 of the adrenergic α1-receptor and the endothelin-A-(ETA)receptor was identified, representing 72.7 % resp. 54.5 % of the patients. AgAAB directed against the angiotensin-1 (AT-1) epitope 1 or 2 were detected in 3 patients and agAAB directed against protease-activated receptor (PAR) loop1/2 were seen in 2 patients. AgAAB directed against ETA-receptor loop1 never appeared without agAAB directed against α1-receptor loop1. Immediately after a five day-course of IA agAAB were absent in 81.8 % of the total study group and in 77.8 % of all cases tested positive for agAAB before IA. Conclusions: AgAAB directed against GPCR were identified in TAO patients with a clustering of agAAB directed against α-1-adrenergic receptor loop1 and ETA-receptor loop1. AgAA were eliminated by IA in the majority of cases. We suggest that these agAA play an important role in the pathogenesis of TAO and that their elimination might be responsible for the positive therapeutic effects reported in patients treated with IA.

scholarly journals Specificity and nanomolar potency of melatonin on G-protein coupled melatonin MT1 and MT2 receptors expressed in HEK-293T human embryo kidney cells

2019 ◽  
Vol 2 (4) ◽  
pp. 121-131 ◽  
Author(s):  
Rafael Rivas-Santisteban ◽  
Irene Reyes-Resina ◽  
Iu Raich ◽  
Jesus J Pintor ◽  
Hanan Awad Alkozi ◽  
...  
Keyword(s):  
G Protein ◽  
Standard Procedure ◽  
G Protein Coupled Receptors ◽  
Prolonged Release ◽  
Therapeutic Effects ◽  
Selective Agonist ◽  
Human Embryo Kidney ◽  
G Protein Coupled ◽  
Camp Levels ◽  
Nanomolar Range

This is a pre-registered study, i.e. a study whose hypotheses and experiments designed to address these hypotheses have been deposited in a database before starting the experiments. The study aims at assessing the Gs versus Gi coupling and the potency of melatonin in the human version of melatonin MT1 and MT2 G-protein-coupled receptors expressed in HEK-293T cells. The results show that these receptors are Gi but not Gs coupled. By using a standard procedure of modulation of 0.5 µM forskolin-induced cAMP levels, it was found that the potency on MT2 receptor-mediated actions is in the low nanomolar range, but the potency on MT1 receptor is in the high nanomolar range.  The potency of melatonin to stimulate the MT2 receptor is similar to that of a selective agonist, N-[2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl)ethyl]butanamide (IIK7). Overall, the data on the potency of melatonin on its receptors will provide a new look for melatonin research. It is important to consider this finding for appropriately addressing physiological or therapeutic effects based on melatonin potency. Thus, the low doses of melatonin used in the existing prolonged release preparations or in other supplements should be revisited.  

scholarly journals Identification of G Protein α Subunit-Palmitoylating Enzyme

2008 ◽  
Vol 29 (2) ◽  
pp. 435-447 ◽  
Author(s):  
Ryouhei Tsutsumi ◽  
Yuko Fukata ◽  
Jun Noritake ◽  
Tsuyoshi Iwanaga ◽  
Franck Perez ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Plasma Membrane ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Fluorescence Recovery After Photobleaching ◽  
G Protein Coupled Receptors ◽  
Α Subunit ◽  
Cytoplasmic Face ◽  
G Protein Α Subunit ◽  
G Protein Coupled

ABSTRACT The heterotrimeric G protein α subunit (Gα) is targeted to the cytoplasmic face of the plasma membrane through reversible lipid palmitoylation and relays signals from G-protein-coupled receptors (GPCRs) to its effectors. By screening 23 DHHC motif (Asp-His-His-Cys) palmitoyl acyl-transferases, we identified DHHC3 and DHHC7 as Gα palmitoylating enzymes. DHHC3 and DHHC7 robustly palmitoylated Gαq, Gαs, and Gαi2 in HEK293T cells. Knockdown of DHHC3 and DHHC7 decreased Gαq/11 palmitoylation and relocalized it from the plasma membrane into the cytoplasm. Photoconversion analysis revealed that Gαq rapidly shuttles between the plasma membrane and the Golgi apparatus, where DHHC3 specifically localizes. Fluorescence recovery after photobleaching studies showed that DHHC3 and DHHC7 are necessary for this continuous Gαq shuttling. Furthermore, DHHC3 and DHHC7 knockdown blocked the α1A-adrenergic receptor/Gαq/11-mediated signaling pathway. Together, our findings revealed that DHHC3 and DHHC7 regulate GPCR-mediated signal transduction by controlling Gα localization to the plasma membrane.

Rab1 interacts directly with the β2-adrenergic receptor to regulate receptor anterograde trafficking

2012 ◽  
Vol 393 (6) ◽  
pp. 541-546 ◽  
Author(s):  
Maha M. Hammad ◽  
Yi-Qun Kuang ◽  
Alexa Morse ◽  
Denis J. Dupré
Keyword(s):  
Endoplasmic Reticulum ◽  
Plasma Membrane ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Direct Interaction ◽  
Potential Interaction ◽  
G Protein Coupled Receptors ◽  
Endocytic Pathway ◽  
Β2 Adrenergic Receptor ◽  
G Protein Coupled

Abstract Very little is understood about the trafficking of G protein-coupled receptors (GPCRs) from the endoplasmic reticulum (ER) to the plasma membrane. Rab guanosine triphosphatases (GTPases) are known to participate in the trafficking of various GPCRs via a direct interaction during the endocytic pathway, but whether this occurs in the anterograde pathway is unknown. We evaluated the potential interaction of Rab1, a GTPase known to regulate β2-adrenergic receptor (β2AR) trafficking, and its effect on export from the ER. Our results show that GTP-bound Rab1 interacts with the F(x)6LL motif of β2AR. Receptors lacking the interaction motif fail to traffic properly, suggesting that a direct interaction with Rab1 is required for β2AR anterograde trafficking.

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