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Endosomal and Lysosomal Electrophysiology
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Xiaoli Zhang, Mingxue Gu, Meiqin Hu, Yexin Yang, Haoxing Xu
Mammalian two-pore channels (TPC1, 2), constituted by two 12 transmembrane subunits (She et al., 2018), are predominantly localized on early endosomes and LELs (Calcraft et al., 2009). TPC2 is believed by many investigators to mediate the NAADP-induced lysosomal Ca2+ release, based on Ca2+ imaging studies (Calcraft et al., 2009; Grimm et al., 2017; Ruas et al., 2015). However, later whole-endolysosome studies suggest that both recombinant and endogenous channels are Na+ selective channels (Wang et al., 2012) (Figure 1.1). TPC’s plant homologues, e.g., AtTPC1, are more permeable to Ca2+ (Guo et al., 2016). Replacement of amino acid residues in the selectivity filter of AtTPC1 by those of human TPC1/2 switches its Ca2+ to Na+ selectivity (Guo et al., 2017). Due to their Na+ selectivity, activation of TPC1/2 effectively changes lysosomal ∆ψ(Wang et al., 2012). TPC1 channels, but not TPC2 channels, are activated at depolarizing voltages and rapidly inactivated at hyperpolarizing voltages (Cang et al., 2014; Wang et al., 2012). Unlike NAADP, PI(3,5)P2 is a well-accepted activator of TPCs (Grimm et al., 2017). In addition, lysosomal TPC2 is likely to be inhibited by mTOR-dependent phosphorylation (Cang et al., 2013). Hence, nutrient-dependent signal transduction may regulate ∆ψthrough TPCs. Studies on TPC knockout (KO) mice suggest that TPCs play important roles under stress, e.g., during Ebola infection and fatty liver hepatitis (Grimm et al., 2014; Sakurai et al., 2015).
The melanocyte and melaninogenesis
Published in Dimitris Rigopoulos, Alexander C. Katoulis, Hyperpigmentation, 2017
Dimitrios Xekardakis, Sabine Krueger-Krasagakis, Konstantinos Krasagakis
Several ion channels seem to have specific roles in melaninogenesis. These channels function at the plasma membrane and at the membrane of intracellular organelles of the melanocytes. The three most important ion channels that operate across the plasma membrane and modulate pigmentation are TRPM1, TRPM7, and TRPA1. They all belong to the transient receptor potential (TRP) channel family. TRPM1 levels are associated with basal pigmentation, according to the fact that a reduction of TRPM1 expression leads to decreased cellular melanin content. TRPM1 expression is controlled by MITF. On the other hand, TRPA1 is activated by ultraviolet A (UVA) and contributes to a rapid increase of melanin. The exact role of TRPM7 in melaninogenesis remains unknown. The most important intracellular ion channels are the endolysosomal TRPML channels, which belong to the mucolipin (ML) subfamily of TRP channels and regulate melanosomal function; the TPC (two-pore channels), which are expressed in acidic organelles and are regulators of melanosomal physiology and pigmentation; and the ClC-7 (chloride channels, isoform 7), which affect the melanosomal differentiation. There are also melanosomal-specific ion channel proteins that regulate at various steps the melaninogenesis that takes place in the melanosome. The most important of them are OCA2, SLC45A2, SLC24A5, and the OA1 ATPases.23 Finally, mitochondrial dynamics regulate melaninogenesis by accelerating degradation of MITF, via modulation of the signaling pathway reactive oxygen species (ROS)–ERK.24
Molecular Mechanisms of Nociception
Published in Gary W. Jay, Chronic Pain, 2007
Potassium channels appear to play an important role in the development of neuronal excitability. There are four families of potassium channels that have different structures, neuropharmacological sensitivities, and functional characteristics: the voltage-gated (KV), calcium activated [K (Ca)], inward rectifier [K (ir)], and the two-pore channels [K (2P)] K (+) (80). Antinociception has been associated with the opening of some forms of these K (+) channels induced by agonists of multiple G-protein coupled receptors, including alpha(2)-adrenoceptors, opioid, GABA(B), muscarinic, serotonin 5HT-1A, nonsteroidal anti inflammatory drugs (NSAIDs), tricyclic antidepressants, and cannabinoid receptors (80). New research indicates that drugs that directly open K (+) channels produce antinociceptive effects in various models of acute and chronic pain (80).
The role of lysosomal ion channels in lysosome dysfunction
Published in Inhalation Toxicology, 2021
Rebekah L. Kendall, Andrij Holian
As the name suggests, two-pore channels (TPCs) consist of two pore domains in a subunit that dimerizes to form a functional pore. TPC1 and TPC2 are localized to endosome and lysosome membranes (Calcraft et al. 2009) and are known to be Ca2+ permeable, but have been shown to be Na+-selective (Figure 2) (Cang et al. 2013; Lagostena et al. 2017). TPC1 is a voltage-gated channel known to be activated by elevated luminal pH, second messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), and PI(3,5)P2 (Calcraft et al. 2009; Wang et al. 2012; Cang et al. 2014). TPC2 is a voltage-independent gated channel (Calcraft et al. 2009). Currently, there is some debate as to the role of the varying activators in initiated TPC activity. Some early evidence indicated that NAADP activates the TPC channels and initiates a Ca2+ efflux, which leads to TFEB translocation (Zhang et al. 2019). Others have indicated that the TCP channel is activated by PI(3,5)P2 and facilitates Na+ movement (Cang et al. 2013). The TPC channel specificity for Na+ over Ca2+ has been confirmed by recent structural studies (Guo et al. 2017). Structural studies have also indicated that PI(3,5)P2 binds directly to amino acid residues in the TPC channels to induce opening (She et al. 2018, 2019). It is possible, that both NAADP and PI(3,5)P2 are TPC activators under specific environmental conditions. Therefore, understanding of the role of each in TPC activity is crucial to understanding the true nature of TPCs’ role in lysosome function.
Targeting calcium-mediated inter-organellar crosstalk in cardiac diseases
Published in Expert Opinion on Therapeutic Targets, 2022
Mohit M. Hulsurkar, Satadru K. Lahiri, Jason Karch, Meng C. Wang, Xander H.T. Wehrens
Lysosomes represent the second largest Ca2+ stores in the cardiomyocytes. There is evidence for continuous crosstalk between the ER/SR and lysosomes mediated by Ca2+ exchange. In ‘anterograde signaling,’ NAADP, a well-known Ca2+-mobilizing second messenger, is known to cause Ca2+ release from the lysosomal two-pore channels (TPC), which results in further Ca2+ release from the SR potentially promoting the development of cardiomyopathies and arrhythmias. Therefore, inhibiting TPC or NAADP function or NAADP synthesis potentially together with RyR2 inhibition could be another novel direction.
Automated patch clamp in drug discovery: major breakthroughs and innovation in the last decade
Published in Expert Opinion on Drug Discovery, 2021
Alison Obergrussberger, Søren Friis, Andrea Brüggemann, Niels Fertig
There is certainly a trend toward using primary cells and stem cells on APC instruments and comparing results across different instruments and techniques, and this includes techniques recording from stem cells grown in a monolayer rather than single cells, e.g. contractility (impedance or contraction force measurements), microelectrode array (MEA), or optical measurements involving voltage-sensitive dyes. Additionally, we have seen a move away from small molecules and more of a movement in the direction of peptides, antibodies, and toxins. Since these materials are usually available only in small quantities, the small volumes required for each well of an HTS APC system coupled with a low number of false positives or false negatives provide a real advantage over other techniques. With the world currently in the grip of a global pandemic with the SARS-CoV-2 virus, new medications and vaccines against this novel coronavirus are being sought in order to treat the infection, prevent the spread of the virus, and ultimately save lives. Could APC play a role in this quest? Almost certainly. Viral proteins are ion channels which could be measured using APC, and other ion-channel targets inhibiting viral entry or preventing a cytokine storm could all be measured using APC. In fact, APC is being employed in the fight against SARS-CoV-2 to find novel compounds or to investigate the effects of repurposed drugs on viral proteins and infection. Also, lysosomal targets such as two-pore channels (TPC) have seen an increase in interest in recent years, not least, as potential anti-viral targets [32]. Indeed, TPCN2 channels in isolated lysosomes have been successfully recorded on small APC devices, e.g. the Port-a-Patch [33], and we see no reason why this could not be scaled up to the larger instruments.