19 research outputs found
Hysteresis and bi-stability by an interplay of calcium oscillations and action potential firing
Many cell types exhibit oscillatory activity, such as repetitive action
potential firing due to the Hodgkin-Huxley dynamics of ion channels in the cell
membrane or reveal intracellular inositol triphosphate (IP) mediated
calcium oscillations (CaOs) by calcium-induced calcium release channels
(IP-receptor) in the membrane of the endoplasmic reticulum (ER). The
dynamics of the excitable membrane and that of the IP-mediated CaOs have
been the subject of many studies. However, the interaction between the
excitable cell membrane and IP-mediated CaOs, which are coupled by
cytosolic calcium which affects the dynamics of both, has not been studied.
This study for the first time applied stability analysis to investigate the
dynamic behavior of a model, which includes both an excitable membrane and an
intracellular IP-mediated calcium oscillator. Taking the IP
concentration as a control parameter, the model exhibits a novel rich spectrum
of stable and unstable states with hysteresis. The four stable states of the
model correspond in detail to previously reported growth-state dependent states
of the membrane potential of normal rat kidney fibroblasts in cell culture. The
hysteresis is most pronounced for experimentally observed parameter values of
the model, suggesting a functional importance of hysteresis. This study shows
that the four growth-dependent cell states may not reflect the behavior of
cells that have differentiated into different cell types with different
properties, but simply reflect four different states of a single cell type,
that is characterized by a single model.Comment: 29 pages, 6 figure
Central CD4+ T cell tolerance: deletion versus regulatory T cell differentiation
The diversion of MHC class II-restricted thymocytes into the regulatory T (Treg) cell lineage, similarly to clonal deletion, is driven by intrathymic encounter of agonist self-antigens. Somewhat paradoxically, it thus seems that the expression of an autoreactive T cell receptor is a shared characteristic of T cells that are subject to clonal deletion and those that are diverted into the Treg cell lineage. Here, we discuss how thymocyte-intrinsic and -extrinsic determinants may specify the choice between these two fundamentally different T cell fates
Autonomous role of medullary thymic epithelial cells in central CD4+ T cell tolerance
International audienceMedullary thymic epithelial cells (mTECs) serve an essential function in central tolerance through expressing peripheral tissue-antigens. These antigens may be transferred to and presented by dendritic cells. Therefore, it is unclear whether mTECs, besides being an 'antigen-reservoir', also serve a mandatory function as antigen presenting cells. Here, we reduced MHC class II on mTECs through transgenic expression of a C2TA-specific 'designer miRNA'. This resulted in an enlarged polyclonal CD4 single-positive compartment and, among thymocytes specific for model-antigens expressed in mTECs, enhanced selection of regulatory T cells (Treg) at the expense of deletion. Our data document an autonomous contribution of mTECs to dominant and recessive mechanisms of CD4+ T cell tolerance and support an avidity model of Treg development versus deletion
Effectiveness of online and mobile telephone applications (‘apps’) for the self-management of suicidal ideation and self-harm: a systematic review and meta-analysis
Stabilizing Role of Calcium Store-Dependent Plasma Membrane Calcium Channels in Action-Potential Firing and Intracellular Calcium Oscillations
In many biological systems, cells display spontaneous calcium oscillations (CaOs) and repetitive action-potential firing. These phenomena have been described separately by models for intracellular inositol trisphosphate (IP(3))-mediated CaOs and for plasma membrane excitability. In this study, we present an integrated model that combines an excitable membrane with an IP(3)-mediated intracellular calcium oscillator. The IP(3) receptor is described as an endoplasmic reticulum (ER) calcium channel with open and close probabilities that depend on the cytoplasmic concentration of IP(3) and Ca(2+). We show that simply combining this ER model for intracellular CaOs with a model for membrane excitability of normal rat kidney (NRK) fibroblasts leads to instability of intracellular calcium dynamics. To ensure stable long-term periodic firing of action potentials and CaOs, it is essential to incorporate calcium transporters controlled by feedback of the ER store filling, for example, store-operated calcium channels in the plasma membrane. For low IP(3) concentrations, our integrated NRK cell model is at rest at −70 mV. For higher IP(3) concentrations, the CaOs become activated and trigger repetitive firing of action potentials. At high IP(3) concentrations, the basal intracellular calcium concentration becomes elevated and the cell is depolarized near −20 mV. These predictions are in agreement with the different proliferative states of cultures of NRK fibroblasts. We postulate that the stabilizing role of calcium channels and/or other calcium transporters controlled by feedback from the ER store is essential for any cell in which calcium signaling by intracellular CaOs involves both ER and plasma membrane calcium fluxes