Molecular mechanisms that appears in chronic hypoxia-induced pulmonary hypertension.
Gonzalez Bosc LV, PhD. Associate Professor. Department of Cell Biology and Physiology. University of New Mexico, USA. http://homeinspectionbronx.nation2.com
Как применять Psorimilk www.rychlapujcka-is.cz/psorimilk/.
Our group in UNM have demonstrated that during chronic hypobaric hypoxia (CH), an event that appears in obstructive chronic pulmonary diseases, endothelin 1 (ET-1) is required in the increase of transcriptional activity of NFATc3. Activated NFATc3 leads Pulmonary Arterial Smooth Muscle Cells proliferation followed by differentiation and hypertrophy, evidenced by up-regulation of α-actin and guanylyl cyclase α-1.
This is the mechanism how appears pulmonary hypertension in those patients.
(1) ET-1 increases Ca2+ release from the endoplasmic reticulum which triggers store-operated Ca2+ entry.
(2) ET-1 inhibits voltage dependent potassium channels (Kv) leading to membrane depolarization and Ca2+ entry through voltage dependent Ca2+ channels (VDCC).
(3) ET-1 decreases superoxide dismutase 1 (SOD1) activity therefore increasing free radical superoxide (O2.-) and decreasing hydrogen peroxide (H2O2) levels. The decrease in H2O2 levels contributes to the activation of acid sensing ion channel 1 (ASIC1) therefore increasing Ca2+ entry.
(4) Ca2+ binds to calmodulin activating calcineurin which dephosphorylates NFATc3 exposing nuclear localization signals. A require step for NFATc3 nuclear translocation and activation.
(5) increased O2.- contributes to activation of RhoA/ROK pathway which increases actin cytoskeleton polymerization contributing to NFATc3 nuclear translocation.
Dynamics of membrane receptors in the cell surface
Rubén Barroso. Departamento de Inmunología y Oncología. Centro Nacional de Biotecnología/CSIC.
There is much evidence of the role played by Chemokines in a multitude of physiological and pathological processes. However, despite the multitude of studies in this field, there are no drugs that blocked the union Chemokine-receptor with a clinical application in the treatment of inflammatory diseases and autoimmune processes in which these proteins are involved. This has forced researchers groups to reassess the biology of these inflammatory mediators in search of new therapeutic targets. In this research we have focused on the conformations of its receivers.
Chemokine receptors are located in the cell surface as homodimers, heterodimers and eben oligomers. They are dynamic structures regulated by the co-expression of own receptors and ligand levels. However, little is known about how the conformations are regulated and what cellular forces govern them. Applying techniques of energy transfer between fluorochromes (FRET, Figures 1A, 1B) and microscopy of total internal reflection (TIRF-M, Figures 2A, 2B) we noticed that CXCR4 form platforms in the cell membrane, the minimum unit is the Dimer.
These platforms are spreading on the lipids in the cell membrane following a model known as "hop-diffusion". Receptors are trapped in membrane compartments defined by the actin cytoskeleton and the proteins that are associated to it, being able to "jump" to adjacent zones where are trapped again. CXCL12, probably promoting the local and temporary reorganization of actin, causes the coalescence of receptors in larger platforms, and this facilitates that response threshold is reached.
Figure 1A. Functioning scheme of FRET technique by “photobleaching”.
Figure 1B. Image of cian fluorescent protein CFP (gives), and yellow, YFP (takes) before and after burning, and FRET calculated as increased fluorescence of CFP.
Figure 2A. Picture of TIRF-M over Jurkat cells elcetroporated with CXCR4 linked to fluorescent preotein, AcGFP (CXCR4-AcGFP).
Figure 2B. Speed of CXCR4 particles (white) related to polimerised actin density (red) in Jurkat cells.