Tuning Supercurrent in Josephson Field-Effect Transistors Using h-BN Dielectric.

Epitaxial Al-InAs heterostructures appear as a promising materials platform for exploring mesoscopic and topological superconductivity. A unique property of Josephson junction field effect transistors (JJ-FETs) fabricated on these heterostructures is the ability to tune the supercurrent using a metallic gate. Here, we report the fabrication and measurement of gate-tunable Al-InAs JJ-FETs in which the gate dielectric in contact with the InAs is produced by mechanically exfoliated hexagonal boron nitride (h-BN) followed by dry transfer.

Phase Signature of Topological Transition in Josephson Junctions.

Topological superconductivity holds promise for fault-tolerant quantum computing. While planar Josephson junctions are attractive candidates to realize this exotic state, direct phase measurements as the fingerprint of the topological transition are missing. By embedding two gate-tunable Al/InAs Josephson junctions in a loop geometry, we measure a π jump in the junction phase with an increasing in-plane magnetic field B_{∥}.

Missing Shapiro steps in topologically trivial Josephson junction on InAs quantum well.

Josephson junctions hosting Majorana fermions have been predicted to exhibit a 4π periodic current phase relation. One experimental consequence of this periodicity is the disappearance of odd steps in Shapiro steps experiments. Experimentally, missing odd Shapiro steps have been observed in a number of materials systems with strong spin-orbit coupling and have been interpreted in the context of topological superconductivity.

Gate controlled anomalous phase shift in Al/InAs Josephson junctions.

In a standard Josephson junction the current is zero when the phase difference between superconducting leads is zero. This condition is protected by parity and time-reversal symmetries. However, the combined presence of spin-orbit coupling and magnetic field breaks these symmetries and can lead to a finite supercurrent even when the phase difference is zero.

Sniffer cells for the detection of neural Angiotensin II in vitro.

Neuropeptide release in the brain has traditionally been difficult to observe. Existing methods lack temporal and spatial resolution that is consistent with the function and size of neurons. We use cultured "sniffer cells" to improve the temporal and spatial resolution of observing neuropeptide release.

Effects of salt-loading on supraoptic vasopressin neurones assessed by ClopHensorN chloride imaging.

Salt-loading (SL) impairs GABA inhibition of arginine vasopressin (AVP) neurones in the supraoptic nucleus (SON) of the hypothalamus. Based on previous studies, we hypothesised that SL activates tyrosine receptor kinase B (TrkB), down-regulating the activity of K /Cl co-transporter2 (KCC2) and up-regulating Na /K /Cl co-transporter1 (NKCC1). These changes in chloride transport would result in increased [Cl ] in SON AVP neurones.

Homer binds to Orai1 and TRPC channels in the neointima and regulates vascular smooth muscle cell migration and proliferation.

The molecular components of store-operated Ca influx channels (SOCs) in proliferative and migratory vascular smooth muscle cells (VSMCs) are quite intricate with many channels contributing to SOCs. They include the Ca-selective Orai1 and members of the transient receptor potential canonical (TRPC) channels, which are activated by the endoplasmic reticulum Ca sensor STIM1. The scaffolding protein Homer assembles SOC complexes, but its role in VSMCs is not well understood.

High glucose and diabetes enhanced store-operated Ca(2+) entry and increased expression of its signaling proteins in mesangial cells.

The present study was conducted to determine whether and how store-operated Ca(2+) entry (SOCE) in glomerular mesangial cells (MCs) was altered by high glucose (HG) and diabetes. Human MCs were treated with either normal glucose or HG for different time periods. Cyclopiazonic acid-induced SOCE was significantly greater in the MCs with 7-day HG treatment and the response was completely abolished by GSK-7975A, a selective inhibitor of store-operated Ca(2+) channels.

Molecular determinants mediating gating of Transient Receptor Potential Canonical (TRPC) channels by stromal interaction molecule 1 (STIM1).

Transient receptor potential canonical (TRPC) channels mediate a critical part of the receptor-evoked Ca(2+) influx. TRPCs are gated open by the endoplasmic reticulum Ca(2+) sensor STIM1. Here we asked which stromal interaction molecule 1 (STIM1) and TRPC domains mediate the interaction between them and how this interaction is used to open the channels.

The STIM1 CTID domain determines access of SARAF to SOAR to regulate Orai1 channel function.

Ca(2+) influx by store-operated Ca(2+) channels (SOCs) mediates all Ca(2+)-dependent cell functions, but excess Ca(2+) influx is highly toxic. The molecular components of SOC are the pore-forming Orai1 channel and the endoplasmic reticulum Ca(2+) sensor STIM1. Slow Ca(2+)-dependent inactivation (SCDI) of Orai1 guards against cell damage, but its molecular mechanism is unknown.

Nuclear factor κB mediates suppression of canonical transient receptor potential 6 expression by reactive oxygen species and protein kinase C in kidney cells.

This study was carried out to explore the molecular mechanism for down-regulation of TRPC6 expression in the reactive oxygen species (ROS)/PKC signaling in kidney cells. In cultured human mesangial cells, H2O2 and TNF-α inhibited TRPC6 mRNA expression in a time-dependent manner. Inhibition of NF-κB reversed both H2O2- and phorbol 12-myristate 13-acetate (PMA)-induced decrease in TRPC6 protein expression.

Canonical transient receptor potential channels in diabetes.

Canonical transient receptor potential (TRPC) channel proteins have been identified as downstream molecules in a G protein-coupled receptor signaling pathway and are involved in a variety of cell functions due to their ability to regulate intracellular calcium signaling. TRPC channel physiology has been an increasingly interesting and relevant topic over the last decade, and the outcomes from various studies have advanced our understanding of TRPC function in the normal state. Recently, attention has turned to whether or not TRPC proteins are implicated in diseases.

The Ca(2+) sensor stromal interaction molecule 1 (STIM1) is necessary and sufficient for the store-operated Ca(2+) entry function of transient receptor potential canonical (TRPC) 1 and 4 channels in endothelial cells.

We addressed the requirement for stromal interaction molecule 1 (STIM1), the endoplasmic reticulum (ER) Ca(2+)-sensor, and Orai1, a Ca(2+) selective channel, in regulating Ca(2+) entry through the store-operated channels mouse transient receptor potential canonical (TRPC) 4 or human TRPC1. Studies were made using murine and human lung endothelial cells (ECs) challenged with thrombin known to induce Ca(2+) entry via TRPC1/4. Deletion or knockdown of TRPC4 abolished Ca(2+) entry secondary to depletion of ER Ca(2+) stores, preventing the disruption of the endothelial barrier.

Opposite regulatory effects of TRPC1 and TRPC5 on neurite outgrowth in PC12 cells.

The transient receptor potential (TRPC) family of Ca²⁺ permeable, non-selective cation channels is abundantly expressed in the brain, and can function as store-operated (SOC) and store-independent channels depending on their interaction with the ER Ca²⁺ sensor STIM1. TRPC1 and TRPC5 have critical roles in neurite outgrowth, however which of their functions regulate neurite outgrowth is unknown. In this study, we investigated the effects of TRPC channels and their STIM1-induced SOC activity on neurite outgrowth of PC12 cells.

STIM1-dependent and STIM1-independent function of transient receptor potential canonical (TRPC) channels tunes their store-operated mode.

Ca(2+) influx by store-operated Ca(2+) channels is a key component of the receptor-evoked Ca(2+) signal. In all cells examined, transient receptor potential canonical (TRPC) channels mediate a significant portion of the receptor-stimulated Ca(2+) influx. Recent studies have revealed how STIM1 activates TRPC1 in response to store depletion; however, the role of STIM1 in TRPC channel activation by receptor stimulation is not fully understood.

Peptidyl-prolyl isomerase FKBP52 controls chemotropic guidance of neuronal growth cones via regulation of TRPC1 channel opening.

Immunophilins, including FK506-binding proteins (FKBPs), are protein chaperones with peptidyl-prolyl isomerase (PPIase) activity. Initially identified as pharmacological receptors for immunosuppressants to regulate immune responses via isomerase-independent mechanisms, FKBPs are most highly expressed in the nervous system, where their physiological function as isomerases remains unknown. We demonstrate that FKBP12 and FKBP52 catalyze cis/trans isomerization of regions of TRPC1 implicated in controlling channel opening.

An endoplasmic reticulum/plasma membrane junction: STIM1/Orai1/TRPCs.

Ca(2+) entering cells through store-operated channels (SOCs) affects most cell functions, and excess SOC is associated with pathologies. The molecular makeup of SOCs and their mechanisms of gating were clarified with the discovery of the Orais and STIM1. Another form of SOCs are the TRPCs.

Molecular determinants of fast Ca2+-dependent inactivation and gating of the Orai channels.

Ca(2+) influx by store-operated Ca(2+) influx channels (SOCs) mediates many cellular functions regulated by Ca(2+), and excessive SOC-mediated Ca(2+) influx is cytotoxic and associated with disease. One form of SOC is the CRAC current that is mediated by Orai channels activated by STIM1. A fundamental property of the native CRAC and of the Orais is fast Ca(2+)-dependent inactivation, which limits Ca(2+) influx to guard against cellular damage.

TRPC channels as STIM1-regulated SOCs.

Store-operated Ca(2+) channels (SOCs) are Ca(2+) influx channels at the plasma membrane whose opening is determined by the level of Ca(2+) stored in the endoplasmic reticulum lumen. SOCs are activated in response to receptor-mediated or passive depletion of ER Ca(2+) to regulate many Ca(2+)-dependent cellular functions. Early work implicated the TRPC channels as SOCs.

Native Store-operated Ca2+ Influx Requires the Channel Function of Orai1 and TRPC1.

With the discovery of STIM1 and Orai1 and gating of both TRPC and Orai1 channels by STIM1, a central question is the role of each of the channels in the native store-operated Ca(2+) influx (SOCs). Here, we used a strategy of knockdown of Orai1 and of TRPC1 alone and in combination and rescue by small interfering RNA-protected mutants (sm) of smOrai1 and smTRPC1 to demonstrate that in human embryonic kidney (HEK) cells, rescue of SOCs required co-transfection of low levels of both smOrai1 and smTRPC1. The pore mutant Orai1(E106Q) failed to rescue the SOCs in the presence or absence of TRPC1 and, surprisingly, the pore mutant TRPC1(F562A) failed to rescue the SOCs in the presence or absence of Orai1.

SOAR and the polybasic STIM1 domains gate and regulate Orai channels.

Influx of Ca(2+) through store-operated Ca(2+) channels (SOCs) is a central component of receptor-evoked Ca(2+) signals. Orai channels are SOCs that are gated by STIM1, a Ca(2+) sensor located in the ER but how it gates and regulates the Orai channels is unknown. Here, we report the molecular basis for gating of Orais by STIM1.

STIM1 gates TRPC channels, but not Orai1, by electrostatic interaction.

The receptor-evoked Ca(2+) signal includes activation of the store-operated channels (SOCs) TRPCs and the Orais. Although both are gated by STIM1, it is not known how STIM1 gates the channels and whether STIM1 gates the TRPCs and Orais by the same mechanism. Here, we report the molecular mechanism by which STIM1 gates TRPC1, which involves interaction between two conserved, negatively charged aspartates in TRPC1((639)DD(640)) with the positively charged STIM1((684)KK(685)) in STIM1 polybasic domain.

Homer proteins in Ca2+ signaling by excitable and non-excitable cells.

Homers are scaffolding proteins that bind Ca(2+) signaling proteins in cellular microdomains. The Homers participate in targeting and localization of Ca(2+) signaling proteins in signaling complexes. However, recent work showed that the Homers are not passive scaffolding proteins, but rather they regulate the activity of several proteins within the Ca(2+) signaling complex in an isoform-specific manner.

TRPC channels as STIM1-regulated store-operated channels.

Receptor-activated Ca(2+) influx is mediated largely by store-operated channels (SOCs). TRPC channels mediate a significant portion of the receptor-activated Ca(2+) influx. However, whether any of the TRPC channels function as a SOC remains controversial.