IP3 Receptor

Dominant variants in WFS1 (wolframin ER transmembrane glycoprotein), the gene coding for a mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein, have been associated with Wolfram-like syndrome (WLS). In vitro and in vivo , WFS1 loss results in reduced ER to mitochondria calcium (Ca2+ ) transfer, mitochondrial dysfunction, and enhanced macroautophagy/autophagy and mitophagy. However, in the WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown...

The 3-mercaptopyruvate sulfurtransferase (MPST) is a protein persulfidase, occurring mainly in mitochondria. Although function of this protein in cancer cells has been already studied, no clear outcome can be postulated up to now. Therefore, we focused on the determination of function of MPST in colon (HCT116 cells)/colorectal (DLD1 cells) cancers. In silico analysis revealed that in gastrointestinal cancers, MPST together with its binding partners can be either of a high risk or might have a protective effect...

The inositol 1,4,5-triphosphate receptor (IP3 R) mediates Ca release in many cell types and is pivotal to a wide range of cellular processes. High resolution cryo-electron microscopy (Cryo-EM) studies have provided new structural details of IP3 R type 1 (IP3 R1), showing that channel function is determined by the movement of various domains within and between each of its four subunits. Channel properties are regulated by ligands, such as Ca and IP3, which bind at specific sites and control the interactions between these domains...

In mammals, three genes encode IP3 receptors (IP3 Rs), which are involved in agonist-induced Ca2+ signaling in cells of apparently all types. Using the CRISPR/Cas9 approach for disruption of two out of three IP3 R genes in HEK-293 cells, we generated three monoclonal cell lines, IP3R1-HEK, IP3R2-HEK, and IP3R3-HEK, with the single functional isoform, IP3 R1, IP3 R2, and IP3 R3, respectively. All engineered cells responded to ACh with Ca2+ transients in an "all-or-nothing" manner, suggesting that each IP3 R isotype was capable of mediating CICR...

Synaptopodin (SP), an actin-associated protein found in telencephalic neurons, affects activity-dependant synaptic plasticity and dynamic changes of dendritic spines. While being required for long-term depression (LTD) mediated by metabotropic glutamate receptor (mGluR-LTD), little is known about its role in other forms of LTD induced by low frequency stimulation (LFS-LTD) or spike-timing dependent plasticity (STDP). Using electrophysiology in ex vivo hippocampal slices from SP-deficient mice (SPKO), we show that absence of SP is associated with a deficit of LTD at Sc-CA1 synapses induced by LFS-LTD and STDP...

The stromal interaction molecules (STIMs) are the sarcoplasmic reticulum (SR) Ca2+ sensors that trigger store-operated Ca2+ entry (SOCE) in a variety of cell types. While STIM1 isoform has been the focus of the research in cardiac pathophysiology, the function of the homolog STIM2 remains unknown. Using Ca2+ imaging and patch-clamp techniques, we showed that knockdown (KD) of STIM2 by siRNAs increased SOCE and the ISOC current in neonatal rat ventricular cardiomyocytes (NRVMs). Within this cardiomyocyte model, we identified the transcript expression of Stim2...

The maintenance of epithelial barrier function involves cellular tension, with cells pulling on their neighbors to maintain epithelial integrity. Wounding interrupts cellular tension, which may serve as an early signal to initiate epithelial repair. To characterize how wounds alter cellular tension, we used a laser-recoil assay to map cortical tension around wounds in the epithelial monolayer of the Drosophila pupal notum.  Within a minute of wounding, there was widespread loss of cortical tension along both radial and tangential directions...

Cell fate is tightly controlled by a continuous balance between cell survival and cell death inducing mechanisms. B-cell lymphoma 2 (Bcl-2)-family members, composed of effectors and regulators, not only control apoptosis at the level of the mitochondria but also by impacting the intracellular Ca2+ homeostasis and dynamics. On the one hand, anti-apoptotic protein Bcl-2, prevents mitochondrial outer membrane permeabilization (MOMP) by scaffolding and neutralizing proapoptotic Bcl-2-family members via its hydrophobic cleft (region composed of BH-domain 1-3)...

Lymphatic collecting vessels exhibit spontaneous phasic contractions that are critical for lymph propulsion and tissue fluid homeostasis. This rhythmic activity is driven by action potentials conducted across the lymphatic muscle cell (LMC) layer to produce entrained contractions. The contraction frequency of a lymphatic collecting vessel displays exquisite mechanosensitivity, with a dynamic range from <1 to >20 contractions per minute. A myogenic pacemaker mechanism intrinsic to the LMCs was initially postulated to account for pressure-dependent chronotropy...

Flopropione (Flo) has been used for gallstone and urolithiasis as a spasmolytic agent almost exclusively in Japan. According to the package insert, its main mechanism is catechol-O-methyltransferase (COMT) inhibition and anti-serotonergic effect. This is obviously contrary to pharmacological common sense, but it is described that way in pharmacology textbooks and occurs in questions in the National Examination for Pharmacists in Japan. As this is a serious problem in education, we re-examined the action of Flo...

Calcium (Ca2+ ) plays a pivotal role in cellular signal transmission by triggering downstream signaling in response to an increase in the cytosolic Ca2+ concentration. Intracellular organelles serve as Ca2+ stores that induce differently shaped Ca2+ signals. We discuss a study by Yuan et al. that investigated the interplay between the lysosomal two-pore channel 2 (TPC2) and endoplasmic reticulum (ER)-localized inositol 1,4,5-trisphosphate receptors (IP3 Rs).

Sour taste is detected by type III taste receptor cells that generate membrane depolarization with action potentials in response to HCl applied to the apical membranes. The shape of action potentials in type III cells exhibits larger afterhyperpolarization due to activation of transient A-type voltage-gated K+ currents. Although action potentials play an important role in neurotransmitter release, the electrophysiological features of A-type K+ currents in taste buds remain unclear. Here, we examined the electrophysiological properties of A-type K+ currents in mouse fungiform taste bud cells using in-situ whole-cell patch clamping...

In skeletal muscle, the Ca2+ release flux elicited by a voltage clamp pulse rises to an early peak that inactivates rapidly to a much lower steady level. Using a double pulse protocol the fast inactivation follows an arithmetic rule: if the conditioning depolarization is less than or equal to the test depolarization, then decay (peak minus steady level) in the conditioning release is approximately equal to suppression (unconditioned minus conditioned peak) of the test release. This is due to quantal activation by voltage, analogous to the quantal activation of IP3 receptor channels...

The recent elegant study by Y. Yuan and colleagues examined functional relationships between the lysosomal two-pore channels 2 (TPC2) and IP3 receptors (IP3Rs) located in the endoplasmic reticulum [1]. The findings of this study suggest functional coupling of these channels and receptors. The study also describes interesting novel phenomena, which may indicate an additional coupling mechanism.

Ferroptosis is an iron-dependent cell death pathway that involves the depletion of intracellular glutathione (GSH) levels and iron-mediated lipid peroxidation. Ferroptosis is experimentally caused by the inhibition of the cystine/glutamate antiporter xCT, which depletes cells of GSH, or by inhibition of glutathione peroxidase 4 (GPx4), a key regulator of lipid peroxidation. The events that occur between GPx4 inhibition and the execution of ferroptotic cell death are currently a matter of active research. Previous work has shown that calcium release from the endoplasmic reticulum (ER) mediated by ryanodine receptor (RyR) channels contributes to ferroptosis-induced cell death in primary hippocampal neurons...

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are clinically linked major neurodegenerative diseases. Notably, TAR DNA-binding protein-43 (TDP43) accumulations are hallmark pathologies of FTD/ALS and mutations in the gene encoding TDP43 cause familial FTD/ALS. There are no cures for FTD/ALS. FTD/ALS display damage to a broad range of physiological functions, many of which are regulated by signaling between the endoplasmic reticulum (ER) and mitochondria. This signaling is mediated by the VAPB-PTPIP51 tethering proteins that serve to recruit regions of ER to the mitochondrial surface so as to facilitate inter-organelle communications...

GPCR-Gi protein pathways are involved in the regulation of vagus muscarinic pathway under physiological conditions and are closely associated with the regulation of internal visceral organs. The muscarinic receptor-operated cationic channel is important in GPCR-Gi protein signal transduction as it decreases heart rate and increases GI rhythm frequency. In the SA node of the heart, acetylcholine binds to the M2 receptor and the released Gβγ activates GIRK (I(K,ACh)) channel, inducing a negative chronotropic action...

The bioenergetic system of calcium ([Ca2+ ]), inositol 1, 4, 5-trisphophate (IP3 ) and nitric oxide (NO) regulate the diverse mechanisms in neurons. The dysregulation in any or all of the calcium, IP3 and nitric oxide dynamics may cause neurotoxicity and cell death. Few studies are noted in the literature on the interactions of two systems like [Ca2+ ] with IP3 and [Ca2+ ] with nitric oxide in neuron cells, which gives limited insights into regulatory and dysregulatory processes in neuron cells. But, no study is available on the cross talk in dynamics of three systems [Ca2+ ], IP3 and NO in neurons...

Steroid hormones play an important role in physiological processes. The classical pathway of steroid actions is mediated by nuclear receptors, which regulate genes to modify biological processes. Non-genomic pathways of steroid actions are also known, mediated by cell membrane-located seven transmembrane domain receptors. Sex steroids and glucocorticoids have several membrane receptors already identified to mediate their rapid actions. However, mineralocorticoids have no identified membrane receptors, although their rapid actions are also measurable...

Calcium signal propagation from endoplasmic reticulum (ER) to mitochondria regulates a multitude of mitochondrial and cell functions, including oxidative ATP production and cell fate decisions. Ca2+ transfer is optimal at the ER-mitochondrial contacts, where inositol 1,4,5-trisphosphate (IP3 ) receptors (IP3R) can locally expose the mitochondrial Ca2+ uniporter (mtCU) to high [Ca2+ ] nanodomains. The Ca2+ loading state of the ER (Ca2 +  ER ) can vary broadly in physiological and pathological scenarios, however, the correlation between Ca2 +  ER and the local Ca2+ transfer is unclear...