Targeting TRPC channels for control of arthritis-induced bone erosion.

Arthritis leads to bone erosion due to an imbalance between osteoclast and osteoblast function. Our prior investigations revealed that the Ca-selective ion channel, Orai1, is critical for osteoclast maturation. Here, we show that the small-molecule ELP-004 preferentially inhibits transient receptor potential canonical (TRPC) channels.

TRPC3: how current mechanistic understanding provides a basis for therapeutic targeting.

Introduction: Intensive and detailed investigations of the molecular function and cellular role of mammalian transient receptor potential canonical (TRPC) channels started back in the early 90 of the past century. Initial TRPC research was fueled by high hopes to resolve fundamental questions of cellular Ca signaling. To date, we have learned important lessons in TRPC channel biology and biophysics, while little progress has been made in terms of therapeutic concepts.

TRPC1: The housekeeper of the hippocampus.

The non-selective cation channel TRPC1 is highly expressed in the brain. Recent research shows that neuronal TRPC1 forms heteromeric complexes with TRPC4 and TRPC5, with a small portion existing as homotetramers, primarily in the ER. Given that most studies have focused on the role of heteromeric TRPC1/4/5 complexes, it is crucial to investigate the specific role of homomeric TRPC1 in maintaining brain homeostasis.

PIP modulates TRPC3 activity via TRP helix and S4-S5 linker.

The transient receptor potential canonical type 3 (TRPC3) channel plays a pivotal role in regulating neuronal excitability in the brain via its constitutive activity. The channel is intricately regulated by lipids and has previously been demonstrated to be positively modulated by PIP. Using molecular dynamics simulations and patch clamp techniques, we reveal that PIP predominantly interacts with TRPC3 at the L3 lipid binding site, located at the intersection of pre-S1 and S1 helices.

Bidirectional Allosteric Coupling between PIP Binding and the Pore of the Oncochannel TRPV6.

The epithelial ion channel TRPV6 plays a pivotal role in calcium homeostasis. Channel function is intricately regulated at different stages, involving the lipid phosphatidylinositol-4,5-bisphosphate (PIP). Given that dysregulation of TRPV6 is associated with various diseases, including different types of cancer, there is a compelling need for its pharmacological targeting.

Nanojunctions: Specificity of Ca signaling requires nano-scale architecture of intracellular membrane contact sites.

Spatio-temporal definition of Ca signals involves the assembly of signaling complexes within the nano-architecture of contact sites between the sarco/endoplasmic reticulum (SR/ER) and the plasma membrane (PM). While the requirement of precise spatial assembly and positioning of the junctional signaling elements is well documented, the role of the nano-scale membrane architecture itself, as an ion-reflecting confinement of the signalling unit, remains as yet elusive. Utilizing the Na/Ca Exchanger-1 / SR/ER Ca ATPase-2-mediated ER Ca refilling process as a junctional signalling paradigm, we provide here the first evidence for an indispensable cellular function of the junctional membrane architecture.

Calcium transport and sensing in TRPC channels - New insights into a complex feedback regulation.

Canonical TRP (TRPC) channels are a still enigmatic family of signaling molecules with multimodal sensing features. These channels enable Ca influx through the plasma membrane to control a diverse range of cellular functions. Based on both regulatory- and recently uncovered structural features, TRPC channels are considered to coordinate Ca and other divalent cations not only within the permeation path but also at additional sensory sites.

Arriving at the next level of complexity in IPR and SOCE signaling.

The endoplasmic reticulum (ER) has long been recognized as the master regulator of cellular Ca signaling. In this context, IPR channels may be envisioned as this conductor's baton, which enables virtuous orchestration of cellular Ca signaling tunes. IPRs serve the generation of spatiotemporally defined Ca changes and are key for the ER´s function as an autonomous Ca signaling unit, which is able to govern its own refilling from the extracellular Ca pool.

TRPC3 governs the spatiotemporal organization of cellular Ca signatures by functional coupling to IP receptors.

Communication between TRPC channels and IP receptors (IPR) is considered pivotal in the generation of spatiotemporal Casignaling patterns. Here we revisited the role of TRPC3-IPR coupling for local Ca signaling within TRPC3-harbouring micro/nanodomains using R-GECO as a reporter, fused to the channel´s C-terminus. Cytoplasmic Ca changes at TRPC3 originated from both the entry of Ca through the TRPC channel and Ca mobilization via IPR.

Differences in circulating obesity-related microRNAs in Austrian and Japanese men: A two-country cohort analysis.

Background: The prevalence of obesity is higher in Western countries than in East Asian countries. It remains unknown whether microRNAs (miRNAs) are involved in the pathogenesis of the ethnic difference in obesity. The purpose of this study was to determine whether expression levels of circulating obesity-associated miRNAs are different in Europeans and Asians.

Exploring TRPC3 Interaction with Cholesterol through Coarse-Grained Molecular Dynamics Simulations.

Transient receptor potential canonical 3 (TRPC3) channel belongs to the superfamily of transient receptor potential (TRP) channels which mediate Ca influx into the cell. These channels constitute essential elements of cellular signalling and have been implicated in a wide range of diseases. TRPC3 is primarily gated by lipids and its surface expression has been shown to be dependent on cholesterol, yet a comprehensive exploration of its interaction with this lipid has thus far not emerged.

Characterization of DAG Binding to TRPC Channels by Target-Dependent Isomerization of OptoDArG.

Azobenzene-based photochromic lipids are valuable probes for the analysis of ion channel-lipid interactions. Rapid photoisomerization of these molecules enables the analysis of lipid gating kinetics and provides information on lipid sensing. Thermal relaxation of the metastable conformation to the conformation of azobenzene photolipids is rather slow in the dark and may be modified by ligand-protein interactions.

Diacylglycerols interact with the L2 lipidation site in TRPC3 to induce a sensitized channel state.

Coordination of lipids within transient receptor potential canonical channels (TRPCs) is essential for their Ca signaling function. Single particle cryo-EM studies identified two lipid interaction sites, designated L1 and L2, which are proposed to accommodate diacylglycerols (DAGs). To explore the role of L1 and L2 in TRPC3 function, we combined structure-guided mutagenesis and electrophysiological recording with molecular dynamics (MD) simulations.

Two-Dimensional Interfacial Exchange Diffusion Has the Potential to Augment Spatiotemporal Precision of Ca Signaling.

Nano-junctions between the endoplasmic reticulum and cytoplasmic surfaces of the plasma membrane and other organelles shape the spatiotemporal features of biological Ca signals. Herein, we propose that 2D Ca exchange diffusion on the negatively charged phospholipid surface lining nano-junctions participates in guiding Ca from its source (channel or carrier) to its target (transport protein or enzyme). Evidence provided by in vitro Ca flux experiments using an artificial phospholipid membrane is presented in support of the above proposed concept, and results from stochastic simulations of Ca trajectories within nano-junctions are discussed in order to substantiate its possible requirements.

TRPC3, an underestimated, universal pacemaker channel?

Transient receptor potential channel canonical 3 (TRPC3) is a cation channel with poor Ca selectivity and significant constitutive activity. One of the channels' features is its striking ability to couple in a surprisingly versatile manner to different down-stream signaling pathways, thereby serving cellular functions in a tissue specific manner. Expression of this protein is prominent in excitable cells, and its activity has repeatedly been implicated in electrical pacemaking.

Ethnic Differences in Serum Levels of microRNAs Potentially Regulating Alcohol Dehydrogenase 1B and Aldehyde Dehydrogenase 2.

Ethnic difference is known in genetic polymorphisms of aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydrogenase 1B (ADH1B), which cause Asian flushing by blood vessel dilation due to accumulation of acetaldehyde. We investigated ethnic differences in microRNAs (miRNAs) related to ALDH2 and ADH1B. miRNA levels in serum were totally analyzed by using miRNA oligo chip arrays and compared in Austrian and Japanese middle-aged men.

Erratum: Potassium ions promote hexokinase-II dependent glycolysis.

[This corrects the article DOI: 10.1016/j.isci.

Potassium ions promote hexokinase-II dependent glycolysis.

High expression levels of mitochondria-associated hexokinase-II (HKII) represent a hallmark of metabolically highly active cells such as fast proliferating cancer cells. Typically, the enzyme provides a crucial metabolic switch towards aerobic glycolysis. By imaging metabolic activities on the single-cell level with genetically encoded fluorescent biosensors, we here demonstrate that HKII activity requires intracellular K.

Pharmaco-Optogenetic Targeting of TRPC Activity Allows for Precise Control Over Mast Cell NFAT Signaling.

Canonical transient receptor potential (TRPC) channels are considered as elements of the immune cell Ca handling machinery. We therefore hypothesized that TRPC photopharmacology may enable uniquely specific modulation of immune responses. Utilizing a recently established TRPC3/6/7 selective, photochromic benzimidazole agonist OptoBI-1, we set out to test this concept for mast cell NFAT signaling.

Mechanisms and significance of Ca entry through TRPC channels.

The transient receptor potential (TRP) superfamily of plasma membrane cation channels has been recognized as a signaling hub in highly diverse settings of human physiopathology. In the past three decades of TRP research, attention was focused mainly on the channels Ca signaling function, albeit additional cellular functions, aside of providing a Ca entry pathway, have been identified. Our understanding of Ca signaling by TRP proteins has recently been advanced by a gain in high-resolution structure information on these pore complexes, and by the development of novel tools to investigate their role in spatiotemporal Ca handling.

Blood levels of microRNAs associated with ischemic heart disease differ between Austrians and Japanese: a pilot study.

Mortality from ischemic heart disease (IHD) is significantly lower in Japan than in Western countries. The purpose of this study was to investigate differences in circulating microRNA (miRNA) levels related to IHD in Austrians and Japanese. Participants were middle-aged healthy male Austrians (n = 20) and Japanese (n = 20).

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.

Light-Mediated Control over TRPC3-Mediated NFAT Signaling.

Canonical transient receptor potential (TRPC) channels were identified as key players in maladaptive remodeling, with nuclear factor of activated T-cells (NFAT) transcription factors serving as downstream targets of TRPC-triggered Ca entry in these pathological processes. Strikingly, the reconstitution of TRPC-NFAT signaling by heterologous expression yielded controversial results. Specifically, nuclear translocation of NFAT1 was found barely responsive to recombinant TRPC3, presumably based on the requirement of certain spatiotemporal signaling features.

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.