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Ion Channels in Human Pluripotent Stem Cells and Their Neural Derivatives
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Ritika Raghavan, Robert Juniewicz, Maharaib Syed, Michael Lin, Peng Jiang
Motor neurons have been mainly derived using cell differentiation method that goes through NPC stages. The differentiated cells exhibited motor neuron gene expression, specifically the expression of HB9 and ChAT genes (55–58). The electrophysiological activity of these neurons was tested at both immature and mature stages. At day 5, the cells had weak APs, low spike magnitude and rate, and did not exhibit bursting activity. At day 21, the cells had faster rising spikes, higher spiking frequency, some bursting behavior, and KV- and NaV-mediated currents (55). Calcium imaging studies confirmed the presence of calcium channels along with spontaneous oscillations of intracellular calcium concentrations. Excitatory postsynaptic potentials (EPSPs) were reduced and inhibited in human motor neurons by the application (2R)-amino-5-phosphonovaleric acid; (2R)-amino-5-phosphonopentanoate (D-AP5) and 6-Cyano-2, 3-dihydroxy-7-nitro-quinoxaline (CNQX), indicating the formation of functional excitatory synapses (56). Inhibitory postsynaptic potentials (IPSPs) could be blocked through the application of strychnine and bicuculline, indicating the expression of functional glycine and GABAA receptors in human motor neurons (56). The expression of Acetylcholine (ACh) channels were tested in hPSC-derived motor neurons co-cultured along with C2C12 myocytes. This showed that hPSC motor neurons can form neuromuscular junctions capable of releasing Ach to initiate muscle contraction (58).
Imaging of Intracellular Calcium in Hippocampal Slices: Methods, Limitations, and Achievements
Published in Avital Schurr, Benjamin M. Rigor, BRAIN SLICES in BASIC and CLINICAL RESEARCH, 2020
Menahem Segal, Jonathan M. Auerbach
Changes in intracellular calcium concentration [Ca2+]i have been assumed to play major roles in plasticity of central neurons. The recent advent of imaging methodologies and the development of high-yield calcium-sensitive fluorescent dyes allow the imaging of [Ca2+]i during responses of the neuron to afferent and chemical stimulation. Herein, we have presented a brief overview of some methods of calcium imaging applied for the analysis of dendritic calcium in central neurons studied in a slice preparation. The advantages and pitfalls of these methods, as well as the main achievements of the studies using calcium imaging have been described.
Advanced Optical Imaging in the Study of Acute and Chronic Response to Implanted Neural Interfaces
Published in Yu Chen, Babak Kateb, Neurophotonics and Brain Mapping, 2017
Cristin G. Welle, Daniel X. Hammer
Functional optical imaging, which resolves physiological activity in addition to anatomy or structure, has a long history with applications in cellular physiology and neuroscience (Cohen et al. 1968; Tasaki et al. 1968). Because of the brain’s architecture of coordinated networks, imaging can provide vastly more information about function than single electrode recordings or even electrode arrays. Functional optical imaging typically involves recording changes in intrinsic absorption and scattering, or more commonly, fluorescent biomarkers. Voltage-sensitive dyes (VSD) rapidly change absorption or emission spectra in response to changes in membrane potential and therefore can be used to optically detect action potentials or other fast cellular dynamics (Civillico 2011). Fluorescent probes based upon calcium binding to proteins are the most commonly used activity-dependent probe. While the application of these methods in neuroscience is immensely important, they have yet to be used extensively to image the biological response to implanted electrodes. Therefore, VSD, calcium imaging, and other functional imaging techniques are not described extensively in this chapter.
The α9α10 nicotinic acetylcholine receptor: a compelling drug target for hearing loss?
Published in Expert Opinion on Therapeutic Targets, 2022
In the absence of α9α10 nAChRs agonists, positive allosteric modulators, appear as the best option. In fact, PAMS of nAChRs in general are considered as a better pharmacotherapeutic tool, since in vivo efficacy of ligands binding to the orthosteric site is limited due to desensitization. This is circumvented by using PAMs, which lack any intrinsic activity, but can enhance the effect of the orthosteric endogenous agonists [143,144,146]. The best example of PAMs used in clinical settings is the benzodiazepines, which enhance GABAA receptor activity, another member of the pentameric ligand-gated ion superfamily [170]. Although no nAChR PAMS has been approved for therapeutics yet, a wide range of them has been developed for neuronal receptors with promising results. The proof of concept that allosteric potentiation of α9α10 nAChRs responses is feasible is provided by the results with ryanodine [164] and the serotonin type 3 receptor agonist 1-(m-chlorophenyl)-biguanide [73]. However, the first next step in order to prove that α9α10 nAChRs PAMS is effective in hearing disorders, is to test them in animal models of noise-induced hearing loss. Moreover, additional α9α10 nAChRs PAMS need to be discovered and tested. This is now facilitated by the recent success in the expression of these receptors in cells coupled to calcium imaging, which allows high-throughput small-molecule screening [165]. Moreover, the known crystal structure of the α9 subunit, coupled to molecular modeling, will aid in deciphering the binding site of PAMS and facilitated further virtual screening for compounds [171].
NiONPs-induced alteration in calcium signaling and mitochondrial function in pulmonary artery endothelial cells involves oxidative stress and TRPV4 channels disruption
Published in Nanotoxicology, 2022
Ophélie Germande, Magalie Baudrimont, Fabien Beaufils, Véronique Freund-Michel, Thomas Ducret, Jean-François Quignard, Marie-Hélène Errera, Sabrina Lacomme, Etienne Gontier, Stéphane Mornet, Megi Bejko, Bernard Muller, Roger Marthan, Christelle Guibert, Juliette Deweirdt, Isabelle Baudrimont
The basal cytoplasmic calcium concentration was measured in HPAEC. After a 4 h and a 24 h-exposure to NiONPs (0.5–5 µg/cm2) calcium imaging was assessed with Fluo-4-AM probe, and the results showed that in HPAEC, after a 4 h-exposure, a significant concentration-dependent increase of the basal cytoplasmic calcium levels was observed (121.17%, 128.1%, and 156.19%, respectively for 0.5, 2.5, and 5 µg/cm2), as compared to untreated cells (Figure 4(A)). Interestingly, after a 24 h-exposure to NiONPS, this significant increase of cytoplasmic calcium levels was still observed (120.34% and 129.74% for 2.5 and 5 µg/cm2, respectively), as compared to untreated cells (Figure 4(B)), suggesting that this alteration of calcium homeostasis was maintained throughout the exposure duration for 2.5 and 5 µg/cm2.
MRGPRX2 is critical for clozapine induced pseudo-allergic reactions
Published in Immunopharmacology and Immunotoxicology, 2021
Di Wei, Tian Hu, Ya-jing Hou, Xiang-jun Wang, Jia-yu Lu, Shuai Ge, Cheng Wang, Huai-zhen He
In pseudo-allergic reactions, mast cells can be directly stimulated by allergens, inducing degranulation and calcium mobilization. We found out that clozapine could promote the release of β-hexosaminidase, histamine and MCP-1 in mast cells, and increase the intracellular calcium ions concentrations. The results of calcium imaging experiment were consistent with the degranulation process, suggesting that increased calcium ions concentrations might promote degranulation. Clozapine was then explored to increase the Evans blue extravasation and paw thickness, and stimulate the release of serum histamine in mice. It was further found that clozapine induced mast cells degranulation and vasodilatation in handpaw skin. Acting as an inflammatory factor, histamine released from mast cells can directly interact with histamine receptor, leading to increased vasodilation and vascular permeability. So, the increased hindpaw inflammation may be related to the increased histamine levels in serum. Based on the above results, we concluded that clozapine could induce pseudo-allergic reactions.