TY  - JOUR
A1  - Chubanov, Vladimir
A1  - Ferioli, Silvia
A1  - Wisnowsky, Annika
A1  - Simmons, David G.
A1  - Leitzinger, Christin
A1  - Einer, Claudia
A1  - Jonas, Wenke
A1  - Shymkiv, Yuriy
A1  - Gudermann, Thomas
A1  - Bartsch, Harald
A1  - Braun, Attila
A1  - Akdogan, Banu
A1  - Mittermeier, Lorenz
A1  - Sytik, Ludmila
A1  - Torben, Friedrich
A1  - Jurinovic, Vindi
A1  - van der Vorst, Emiel P. C.
A1  - Weber, Christian
A1  - Yildirim, Önder A.
A1  - Sotlar, Karl
A1  - Schürmann, Annette
A1  - Zierler, Susanna
A1  - Zischka, Hans
A1  - Ryazanov, Alexey G.
T1  - Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival
JF  - eLife
N2  - Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood.
KW  - signalling pathways
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164987
VL  - 5
ER  - 
TY  - JOUR
A1  - Stritt, Simon
A1  - Nurden, Paquita
A1  - Favier, Remi
A1  - Favier, Marie
A1  - Ferioli, Silvia
A1  - Gotru, Sanjeev K.
A1  - van Eeuwijk, Judith M.M.
A1  - Schulze, Harald
A1  - Nurden, Alan T.
A1  - Lambert, Michele P.
A1  - Turro, Ernest
A1  - Burger-Stritt, Stephanie
A1  - Matsushita, Masayuki
A1  - Mittermeier, Lorenz
A1  - Ballerini, Paola
A1  - Zierler, Susanna
A1  - Laffan, Michael A.
A1  - Chubanov, Vladimir
A1  - Gudermann, Thomas
A1  - Nieswandt, Bernhard
A1  - Braun, Attila
T1  - Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg\(^{2+}\) homeostasis and cytoskeletal architecture
JF  - Nature Communications
N2  - Mg\(^{2+}\) plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg\(^{2+}\)]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7\(^{fl/fl-Pf4Cre}\)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7\(^{fl/fl-Pf4Cre}\) MKs, which is rescued by Mg\(^{2+}\) supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.
KW  - Cytoskeleton
KW  - homeostasisIon channels
KW  - thrombopoiesis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173843
VL  - 7
ER  - 
TY  - JOUR
A1  - Han, Chao
A1  - Ren, Pengxuan
A1  - Mamtimin, Medina
A1  - Kruk, Linus
A1  - Sarukhanyan, Edita
A1  - Li, Chenyu
A1  - Anders, Hans-Joachim
A1  - Dandekar, Thomas
A1  - Krueger, Irena
A1  - Elvers, Margitta
A1  - Goebel, Silvia
A1  - Adler, Kristin
A1  - Münch, Götz
A1  - Gudermann, Thomas
A1  - Braun, Attila
A1  - Mammadova-Bach, Elmina
T1  - Minimal collagen-binding epitope of glycoprotein VI in human and mouse platelets
JF  - Biomedicines
N2  - Glycoprotein VI (GPVI) is a platelet-specific receptor for collagen and fibrin, regulating important platelet functions such as platelet adhesion and thrombus growth. Although the blockade of GPVI function is widely recognized as a potent anti-thrombotic approach, there are limited studies focused on site-specific targeting of GPVI. Using computational modeling and bioinformatics, we analyzed collagen- and CRP-binding surfaces of GPVI monomers and dimers, and compared the interacting surfaces with other mammalian GPVI isoforms. We could predict a minimal collagen-binding epitope of GPVI dimer and designed an EA-20 antibody that recognizes a linear epitope of this surface. Using platelets and whole blood samples donated from wild-type and humanized GPVI transgenic mice and also humans, our experimental results show that the EA-20 antibody inhibits platelet adhesion and aggregation in response to collagen and CRP, but not to fibrin. The EA-20 antibody also prevents thrombus formation in whole blood, on the collagen-coated surface, in arterial flow conditions. We also show that EA-20 does not influence GPVI clustering or receptor shedding. Therefore, we propose that blockade of this minimal collagen-binding epitope of GPVI with the EA-20 antibody could represent a new anti-thrombotic approach by inhibiting specific interactions between GPVI and the collagen matrix.
KW  - GPVI
KW  - collagen
KW  - blood platelets
KW  - thrombosis
KW  - anti-thrombotic therapies
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304148
SN  - 2227-9059
VL  - 11
IS  - 2
ER  -