The bioelectric mechanisms of local calcium dynamics in cancer cell proliferation: an extension of the A549 cell model.

Introduction: Advances in molecular targeting of ion channels may open up new avenues for therapeutic approaches in cancer based on the cells' bioelectric properties. In addition to or models, models can provide deeper insight into the complex role of electrophysiology in cancer and reveal the impact of altered ion channel expression and the membrane potential on malignant processes. The A549 model is the first computational cancer whole-cell ion current model that simulates the bioelectric mechanisms of the human non-small cell lung cancer cell line A549 during the different phases of the cell cycle.

Shedding Light on Cardiac Excitation: In Vitro and In Silico Analysis of Native Ca Channel Activation in Guinea Pig Cardiomyocytes Using Organic Photovoltaic Devices.

Objective: This study aims to explore the potential of organic electrolytic photocapacitors (OEPCs), an innovative photovoltaic device, in mediating the activation of native voltage-gated Cav1.2 channels (I) in Guinea pig ventricular cardiomyocytes.

Methods: Whole-cell patch-clamp recordings were employed to examine light-triggered OEPC mediated I activation, integrating the channel's kinetic properties into a multicompartment cell model to take intracellular ion concentrations into account.

Lipopolysaccharide-induced sepsis impairs M2R-GIRK signaling in the mouse sinoatrial node.

Sepsis has emerged as a global health burden associated with multiple organ dysfunction and 20% mortality rate in patients. Numerous clinical studies over the past two decades have correlated the disease severity and mortality in septic patients with impaired heart rate variability (HRV), as a consequence of impaired chronotropic response of sinoatrial node (SAN) pacemaker activity to vagal/parasympathetic stimulation. However, the molecular mechanism(s) downstream to parasympathetic inputs have not been investigated yet in sepsis, particularly in the SAN.

A549 in-silico 1.0: A first computational model to simulate cell cycle dependent ion current modulation in the human lung adenocarcinoma.

Lung cancer is still a leading cause of death worldwide. In recent years, knowledge has been obtained of the mechanisms modulating ion channel kinetics and thus of cell bioelectric properties, which is promising for oncological biomarkers and targets. The complex interplay of channel expression and its consequences on malignant processes, however, is still insufficiently understood.

Modeling External Stimulation of Excitable Cells Using a Novel Light-Activated Organic Semiconductor Technology.

Optoelectronic neurostimulation is a promising, minimally invasive treatment modality for neuronal damage, in particular for patients with traumatic brain injury. In this work, a newly developed optoelectronic device, a so-called photocap, based on light-activated organic semiconductor structures with high spatial and temporal resolution is investigated. To prove and verify the feasibility of this new technology, a mathematical model was developed, simulating the electrical response of excitable cells to photocap stimulation.

TRIC-A shapes oscillatory Ca2+ signals by interaction with STIM1/Orai1 complexes.

Trimeric intracellular cation (TRIC) channels have been proposed to modulate Ca2+ release from the endoplasmic reticulum (ER) and determine oscillatory Ca2+ signals. Here, we report that TRIC-A-mediated amplitude and frequency modulation of ryanodine receptor 2 (RyR2)-mediated Ca2+ oscillations and inositol 1,4,5-triphosphate receptor (IP3R)-induced cytosolic signals is based on attenuating store-operated Ca2+ entry (SOCE). Further, TRIC-A-dependent delay in ER Ca2+ store refilling contributes to shaping the pattern of Ca2+ oscillations.

Lipid-independent control of endothelial and neuronal TRPC3 channels by light.

Lipid-gated TRPC channels are highly expressed in cardiovascular and neuronal tissues. Exerting precise pharmacological control over their activity in native cells is expected to serve as a basis for the development of novel therapies. Here we report on a new photopharmacological tool that enables manipulation of TRPC3 channels by light, in a manner independent of lipid metabolism and with higher temporal precision than lipid photopharmacology.

Saxagliptin but Not Sitagliptin Inhibits CaMKII and PKC via DPP9 Inhibition in Cardiomyocytes.

Some oral anti-hyperglycemic drugs, including gliptins that inhibit dipeptidyl peptidase 4 (DPP4), have been linked to the increased risk of heart failure (HF) in type-2 diabetic patients. While the cardiovascular safety trial, TECOS, revealed no link between sitagliptin and the risk of HF, a substantial 27% increase in the hospitalization for HF was observed in type-2 diabetic patients treated with saxagliptin within the SAVOR-TIMI 53 trial. A previous study revealed that saxagliptin impairs the Ca/calmodulin-dependent protein kinase II (CaMKII)-phospholamban (PLB)-sarcoplasmic reticulum Ca-ATPase 2a axis and protein kinase C (PKC) activity in cardiomyocytes leading to impaired cardiac contractility and electrophysiological function.

An optically controlled probe identifies lipid-gating fenestrations within the TRPC3 channel.

Transient receptor potential canonical (TRPC) channels TRPC3, TRPC6 and TRPC7 are able to sense the lipid messenger diacylglycerol (DAG). The DAG-sensing and lipid-gating processes in these ion channels are still unknown. To gain insights into the lipid-sensing principle, we generated a DAG photoswitch, OptoDArG, that enabled efficient control of TRPC3 by light.

Cardiovascular and Hemostatic Disorders: SOCE in Cardiovascular Cells: Emerging Targets for Therapeutic Intervention.

The discovery of the store-operated Ca entry (SOCE) phenomenon is tightly associated with its recognition as a pathway of high (patho)physiological significance in the cardiovascular system. Early on, SOCE has been investigated primarily in non-excitable cell types, and the vascular endothelium received particular attention, while a role of SOCE in excitable cells, specifically cardiac myocytes and pacemakers, was initially ignored and remains largely enigmatic even to date. With the recent gain in knowledge on the molecular components of SOCE as well as their cellular organization within nanodomains, potential tissue/cell type-dependent heterogeneity of the SOCE machinery along with high specificity of linkage to downstream signaling pathways emerged for cardiovascular cells.

Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure.

Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca-ATPase 2a axis and Na-Ca exchanger function in Ca extrusion.

Na /Ca exchangers and Orai channels jointly refill endoplasmic reticulum (ER) Ca via ER nanojunctions in vascular endothelial cells.

We investigated the role of Na/ Ca exchange (NCX) in the refilling of endoplasmic reticulum (ER) Ca in vascular endothelial cells under various conditions of cell stimulation and plasma membrane (PM) polarization. Better understanding of the mechanisms behind basic ER Ca content regulation is important, since current hypotheses on the possible ultimate causes of ER stress point to deterioration of the Ca transport mechanism to/from ER itself. We measured [Ca] temporal changes by Fura-2 fluorescence under experimental protocols that inhibit a host of transporters (NCX, Orai, non-selective transient receptor potential canonical (TRPC) channels, sarco/endoplasmic reticulum Ca ATPase (SERCA), Na/ K ATPase (NKA)) involved in the Ca communication between the extracellular space and the ER.

Corrigendum: Pharmacological Characterization of the Native Store-Operated Calcium Channels of Cortical Neurons from Embryonic Mouse Brain.

[This corrects the article on p. 486 in vol. 7, PMID: 28018223.

Pharmacological Characterization of the Native Store-Operated Calcium Channels of Cortical Neurons from Embryonic Mouse Brain.

In the murine brain, the first post-mitotic cortical neurons formed during embryogenesis express store-operated channels (SOCs) sensitive to Pyr3, initially proposed as a blocker of the transient receptor potential channel of C type 3 (TRPC3 channel). However, Pyr3 does not discriminate between Orai and TRPC3 channels, questioning the contribution of TRPC3 in SOCs. This study was undertaken to clarify the molecular identity and the pharmacological profile of native SOCs from E13 cortical neurons.