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Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
Like all the other TRP channels (Nilius et al., 2007; Ramsey et al., 2006), TRPML proteins form tetramers, and each pore-forming subunit contains six transmembrane segments (S1-S6) or six transmembrane domains (TM1-TM6) that are separated into an S1-S4 voltage-sensing domain (VSD) and an S5-S6 pore region (P). Distinct from other TRP channels, TRPMLs are characterized by a large extracellular (or intraluminal) loop between S1 and S2 and intracellular endolysosomal localization that is determined by dileucine motifs and their heteromultimerization (Venkatachalam et al., 2006; Vergarajauregui and Puertollano, 2006). Functionally, TRPMLs are inwardly (cation flowing from the lumen to the cytosol) rectifying channels permeable to both Ca2+ and Na+ (Chen et al., 2017; Dong et al., 2008; Plesch et al., 2018). Given the presumed topology of TRPML proteins at the endolysosomal membrane and the electrical properties of the lysosome, TRPML opening leads to Ca2+ and Na+ release from the endolysosome to the cytosol (Chen et al., 2017; Dong et al., 2008, 2010) (Figure 18.3). Additionally, TRPML1 and TRPML2 are also permeable to heavy trace metals such as Fe2+ and Zn2+ (Dong et al., 2008; Eichelsdoerfer et al., 2010).
TRPML Subfamily of Endolysosomal Channels
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Nicholas E. Karagas, Morgan A. Rousseau, Kartik Venkatachalam
There are several compounds that either directly or indirectly influence the activity of TRPML channels, and therefore, permit the rapid investigation of channel function in a multitude of contexts. The first TRPML inhibitor, mucolipin synthetic inhibitor 1 (ML-SI1), also known as GW-405833, was originally found to be a selective partial agonist of the endocannabinoid receptors, CB2 and CB1, having a weaker affinity for the latter (Clayton et al., 2002). In addition to its action on endocannabinoid receptors, ML-SI1 is an antagonist of TRPML1 (Samie et al., 2013; Wang et al., 2015). Since the description of ML-SI1, newer generation TRPML1 antagonists with relatively higher specificity have been developed (Kilpatrick et al., 2016; Samie et al., 2013). These compounds are particularly valuable because many conventional cation channel blockers are not effective inhibitors of TRPML1. Given that TRPML channels are activated by PI(3,5)P2, inhibitors of the enzyme involved in the biogenesis of this endolysosomal phosphoinositide – Pikfyve – are indirect inhibitors of TRPML activity. In this context, YM201636 and apilimod are Pikfyve inhibitors that inhibit TRPML-mediated endolysosomal Ca2+ release (Dong et al., 2010; Lee et al., 2015; Wong et al., 2017). Direct TRPML agonists have also been described. First in this class was a compound named mucolipin synthetic agonist 1 (ML-SA1) (Shen et al., 2012). Other drugs that act on TRPML1, as well as TRPML2 and TRPML3, have also been described (Chen et al., 2014; Grimm et al., 2010, 2012). The utility of these drugs is highlighted by the fact that they are all cell-permeable and can be added to the extracellular media to influence channel activity within cells. Alternatively, we have found that mixing these drugs into fly food is an effective approach to inhibit the activity of TRPML in Drosophila (unpublished observations).
Associations between weather conditions and osteoarthritis pain: a systematic review and meta-analysis
Published in Annals of Medicine, 2023
Lin Wang, Qinguang Xu, Yan Chen, Zhaohua Zhu, Yuelong Cao
Our finding may have broad applicability to those OA patients who are more vulnerable to weather conditions. An early European study reported that 67.2% of participants with OA attributed their pain to the weather [15]. Evidence from recent study also demonstrated the association of weather sensitivity and clinical symptoms and structural degradations in knee OA patients. 57.5% of weather-sensitive individuals more likely had severe knee pain, dysfunction and as well as cartilage defects [16]. When clinical research evidence increasingly demonstrates the aggravation of weather conditions such as T, RH and BP on OA pain, weather factors should be considered in OA management. Our finding may also contribute to the development of basic research on weather impacting OA pain. The function of Thermosensitive Transient Receptor Potential channels (Thermo-TRPs) was related with the weather stimulating, which may be the possible pathophysiological mechanisms of OA pain [44–47]. TRPs are a large family of proteins including 6 main subfamilies termed the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and TRPA (ankyrin) groups [48]. Andersson reported the TRPA-1 was overexpressed after exposure to cold temperatures (10 °C), and the mice demonstrated more nocifensive behaviour and mechanical pain sensitivity [49,50]. These quantitative analysis findings, positive or negative effect of BP, RH, and T on OA pain, may provide the basic theories and help to set weather parameters for future studies exploring these potential mechanisms.
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
TRPML channels are widely considered to be the main mechanism through which Ca2+ is released from the lysosome [182,183]. The TRPML family of proteins consists of three members, TRPML1, TRPML2 and TRPML3. Each of them has six transmembrane domains (TM1 to TM6) and these proteins assemble as tetramers to form a pore across the lysosomal membrane [182,183]. TRPML1 is ubiquitously expressed, while TRPML2 and TRPML3 are expressed in selective tissues and are localized on the recycling or early endosomes [171]. TRPML1 is a nonselective cation channel that is activated by ligand binding. Cryo-electron microscopy studies revealed that phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) binds to the N terminus of the channel and is a potent TRPML1 agonist. While a direct role and mechanisms of TRPML1 in cardiac diseases is not yet uncovered, it regulates multiple cellular processes like autophagy, exocytosis and membrane trafficking [182,183] and the impairment in the TRPML1 function leads to various lysosomal storage diseases [184], which ultimately results in multiple cardiac disorders including dilated and hypertrophic cardiomyopathy [185].
Redox-sensitive TRP channels: a promising pharmacological target in chemotherapy-induced peripheral neuropathy
Published in Expert Opinion on Therapeutic Targets, 2021
Ramandeep Singh, Pratik Adhya, Shyam Sunder Sharma
TRP channels are category of nonselective cation channels involved in the signaling of diverse physical and chemical stimuli. They are categorized into six sub-families: TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPV (vanilloid), TRPP (polycystin), and TRPML (mucolipin), based on their sequence homology [7]. TRP channels are not only involved in pain, taste, thermal, and mechanosensation but they are also involved in several pathological conditions like neurodegenerative disorders, neuropathic pain, cardiac disorders, renal disorders, and cancer [8–11]. Even, TRPs can also be divided into thermosensing TRPs, mechanosensing TRPs, and redox sensing TRPs based on the mechanism of their activation. Amongst them redox sensing TRPs or redox TRPs is one of the crucial targets in CIPN on account of their potential to be activated by oxidative stress conditions. Redox TRPs are activated through modification of cysteine, methionine residues present in the pore-forming regions or through ADPR on binding to the NUDT9-H domain.