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Substrates of Human CYP2D6
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
Oral hypoglycemic drugs include the sulfonylureas (e.g., glipizide, glimepiride, and glyburide) and biguanides (e.g., met-formin, buformin, and phenformin), which are currently used in the treatment of type II diabetes (Marchetti et al. 1991).
Cytoskeletons (F-actin) and spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
Liza O’Donnell, Peter G. Stanton
Finally, it should also be noted that there is extensive cross talk between the actin and microtubule cytoskeletons.12 For example, while cell motility requires actin polymerization in membrane protrusions, directional cell movement involves growing microtubules being captured by the cortical actin foci at the leading edge of the cell.12 Actin-binding formins appear to be a key player in the cross talk between the actin and microtubule cytoskeleton, with an ability to regulate both actin polymerization and microtubule stabilization.13
AGE-RAGE Axis in the Aging and Diabetic Heart
Published in Sara C. Zapico, Mechanisms Linking Aging, Diseases and Biological Age Estimation, 2017
Karen M. O’Shea, Ann Marie Schmidt, Ravichandran Ramasamy
The precise consequences of RAGE signaling vary based on cell type, as well as duration of RAGE stimulation. RAGE transduces extracellular signals through ligand binding to its 332-amino acid extracellular component, consisting of 2 “C”-type domains preceded by 1 “V”-type immunoglobulin-like domain (Yan et al. 2003). RAGE also contains a transmembrane domain and a highly charged 43-amino acid cytosolic tail, which is responsible for mediating intracellular signaling (Schmidt et al. 2001). While the precise mechanisms of intracellular RAGE signaling have not been fully elucidated, the cytosolic tail interacts with the formin protein, Diaph1 (also known as mDia1 or Drf1) (Hudson et al. 2008). The cytosolic domain of RAGE is critical for RAGE-dependent signaling and modulation of gene expression. When the cytosolic domain is deleted, this imparts a “dominant negative” effect; although cells may bind ligand, ligands are not able to activate RAGE signaling (Bucciarelli et al. 2008, Harja et al. 2008).
Loss of mDia1 and Fhod1 impacts platelet formation but not platelet function
Published in Platelets, 2021
Malou Zuidscherwoude, Elizabeth J. Haining, Victoria A. Simms, Stephanie Watson, Beata Grygielska, Alex T. Hardy, Andrea Bacon, Stephen P. Watson, Steven G. Thomas
Formins are a class of actin-binding proteins known as nucleation-promoting factors, although they have been shown to have functions beyond simple nucleation. Members of the formin protein family have the ability to both nucleate and accelerate the elongation of linear actin fibers and are also involved in microtubule dynamics and organization [12]. Formins are increasingly recognized as regulators of cross-talk between the actin and microtubule cytoskeletons and they can therefore be expected to play a role in multiple aspects of platelet formation and function [13]. Indeed, a gain of function variant of formin mDia1 (DIAPH1) is linked to macrothrombocytopenia in humans [14,15]. Of the 15 mammalian formins, only 4 are expressed in platelets and megakaryocytes, namely mDia1, Fhod1, Daam1, and Inf2 which contribute 24.5%, 36.7%, 14.5%, and 24.3%, respectively, of the total formin protein expressed in mouse platelets [13,16]. We have previously shown that platelets from an mDia1 knockout mouse were functionally normal and hypothesize that this was due to redundant function with other platelet/megakaryocyte expressed formin family members [16]. In support of this, we have recently reported that blocking formin FH2 domains using a small molecule inhibitor (SMIFH2) completely abolishes platelet spreading and disrupts microtubule dynamics [17], highlighting the role of formins in regulating both actin and microtubule platelet cytoskeletons.
Characterization of cell-cell junction changes associated with the formation of a strong endothelial barrier
Published in Tissue Barriers, 2018
MaryPeace McRae, Lindsay M. LaFratta, Benjamin M. Nguyen, Jason J. Paris, Kurt F. Hauser, Daniel E. Conway
In our studies, we observed that HUVEC cells cultured in medium supplemented with cAMP analogues resulted in a tighter barrier, as measured by an increased cellular TEER. On a similar timescale, these cells also displayed increases in ZO-1 and VE-cadherin expression, vinculin recruitment to cell-cell junctions, and decreased cell-cell junctional force. Furthermore, we observed that endothelial cells cultured with cAMP supplementation exhibited more cortical actin, whereas control cells had more stress fiber actin distribution. These data are consistent with stronger adhesion junctions in the cAMP supplemented groups. Others have demonstrated that actin tethering to adhesion complexes is necessary for the formation and stabilization of intercellular junctions.33 Conversely, agents known to disrupt actin tethering (like thrombin and histamine) can result in actin reorganization from the cell cortex into stress fibers that stretch across the cell body. The stress fibers produce a tensile force to pull proteins away from the cell surface inward toward the center of the cell, creating a compromised barrier.33 Our data is consistent with these findings. In these studies, cells were treated with SMIFH2, an inhibitor of formin. Formins act to promote the assembly of linear actin filaments and promote stress fiber formation.34,35 Inhibition of stress fiber formation by SMIFH2 resulted in an increased TEER, consistent with enhanced barrier function.
Formin proteins in megakaryocytes and platelets: regulation of actin and microtubule dynamics
Published in Platelets, 2019
Malou Zuidscherwoude, Hannah L.H. Green, Steven G. Thomas
Formin proteins exist in an auto-inhibited state. Diaphanous-related formins (DRFs) contain conserved regulatory domains; a C-terminal Diaphanous Auto-regulatory Domain (DAD) and an N-terminal Diaphanous Inhibitory Domain (DID – which forms part of the FH3 domain) (11). Intramolecular interactions between the DAD and DID lead to auto-inhibition of formin activity (Figure 1(d)). As a general rule, this auto-inhibition can be relieved upon the interaction of the GTPase-binding domain (GBD) with an active Rho GTPase (12). Therefore, Rho GTPases recruit formins to different locations within the cell for localised actin filament assembly.