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Endolysosomal Cation Channels As Therapeutic Targets—Pharmacology of TRPML Channels

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Endolysosomal Cation Channels As Therapeutic Targets—Pharmacology of TRPML Channels Review Copyright © 2016 American Scientific Publishers MESSENGER Vol. 5, 30–36, 2016 All rights reserved www.aspbs.com/messenger Printed in the United States of America Endolysosomal Cation Channels as Therapeutic Targets—Pharmacology of TRPML Channels Christian Grimm Munich Center for Integrated Protein Science CIPSM and Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universität München, 81377, Germany In recent years it has become more and more accepted that the endolysosomal system (ES) plays a key role for human health. Dysfunction of the ES has been found to be implicated in a range of human diseases ranging MESSENGER from infectious and metabolic to lysosomal storage, retinal and neurodegenerative diseases. Results obtained from animal models and human mutations have also spurred the interest in endolysosomal membrane proteins. In particular, the study of endolysosomal ion channels as potential novel drug targets for the treatment of various diseases has gained momentum with recently established endolysosomal patch-clamp techniques. These tech- niques now allow functional characterization of these organellar membrane proteins in more detail. Another key development was the discovery of small molecule agonists and antagonists to pharmacologically interfere with these endolysosomal ion channels in vitro and in vivo. This review gives an overview of the currently available small molecule agonists and antagonists of one major group of endolysosomal cation channels, the mucolipins or TRPML channels and how they have helped to speed up research in the field. Keywords: Calcium, TRPML, MCOLN, TRPML1, Mucolipin. MESSENGER MESSENGER IP: 192.168.39.151 On: Thu, 30 Sep 2021 22:36:36 Copyright: American Scientific Publishers CONTENTS Delivered byand Ingenta neurodegenerative diseases, retinal and pigmentation disorders, trace metal dishomeostasis and infectious dis- Introduction ............................................30 eases (Fig. 1(A)). Besides soluble proteins in the matrix Discovery of Small Molecule Agonists and Antagonists of TRPMLChannels .......................................32 of endolysosomal organelles, endolysosomal membrane SmallMoleculesLinkTRPMLFunctionwithPhysiology.........32 proteins, in particular endolysosomal ion channels and Species-DependentEffectsofTRPMLChannelOpeners..........34 transport proteins are increasingly recognized as impor- TRPMLChannelsasTherapeuticTargets .....................35 tant regulators of endolysosomal function. Thus, they are Conclusion.............................................35 highly critical for the regulation of ionic concentrations Acknowledgment......................................35 References...........................................35 within the endolysosomal vesicle lumen and they partic- MESSENGER ipate in the regulation of the numerous endolysosomal vesicle trafficking processes. They also participate in the INTRODUCTION regulation of phagocytosis, lysosomal exocytosis, lysoso- mal vesicle motility, metal homeostasis, lysosomal pH, Endosomes and lysosomes are cell organelles known autophagosome-lysosome fusion and lysosome reforma- to be involved in transport, breakdown and secre- tion from autolysosomes (Dong et al., 2010; Samie et al., tion of lipids, proteins, and other macromolecules. The 2013; Grimm et al., 2014; Bae et al., 2014; Sakurai et al., endolysosomal system (ES) as it is found in almost 2015; Patel et al., 2015; Li et al., 2016; Park et al., 2016). every cell of the human body consists in particular of Very recently also a link between oxidative stress, ROS early endosomes (EE), recycling endosomes (RE), late (reactive oxygen species) and TRPML channels has been endosomes (LE), and lysosomes (LY). Endolysosomal MESSENGER established (Zhang et al., 2016; Kiselyov and Muallem, dysfunction can cause multiple storage disorders such as 2016). mucolipidoses, sphingolipidoses or neuronal ceroid lipo- The endolysosomal channelome/transportome which fuscinoses (NCL), which typically go along with fatal comprises at least 70 different proteins (Schwake et al., neurodegenerative processes. Dysfunction of the ES has 2013; Chapel et al., 2013) is however, with few exceptions also been implicated in the development of metabolic still “terra incognita” (Fig. 1(B)). With recent advances in endolysosomal patch-clamp technology, it has now E-mail: [email protected] become possible to directly investigate the biophysical 30 MESSENGER 2016, Vol. 5, No. 1/2 2167-955X/2016/5/030/007 doi:10.1166/msr.2016.1061 MESSENGER MESSENGER Grimm Endolysosomal Cation Channels as Therapeutic Targets—Pharmacology of TRPML Channels MESSENGER MESSENGER IP: 192.168.39.151 On: Thu, 30 Sep 2021 22:36:36 Copyright: American Scientific Publishers Delivered by Ingenta MESSENGER MESSENGER Figure 1. The endolysosmal system and the endolysosomal transportome. (A) The endolysosomal system (ES) as it is found in almost every cell of the human body, typically consists of early endosomes (EE), late endosomes (LE), and lysosomes (LY). In addition, recycling endosomes, autophagosomes, and multivesicular bodies are also part of the ES (not shown here). The ES is required for the intracellular transport, recycling and degradation of receptors and other macromolecules as well as trace metals such as iron or zinc. Other important cell-dependent functional roles of the ES are lysosomal exocytosis and phagocytosis. (B) Endolysosomal ion channels such as TRPML channels (TRPML1, 2 and 3) or two-pore channels (TPC1 and TPC2) have recently emerged as important regulators of trafficking and fusion processes within the ES and appear to be essential for a proper communication between the various endolysosomal organelles. Their biophysical properties and ion channel characteristics have been well described while the vast majority of the proteins of the endolysosomal transportome is not characterized yet. MESSENGER properties and thus the physiological roles of endolysoso- channel family, namely the endolysosomal TRPML chan- mal ion channels with important implications for diseases nels (TRPML1-3), also called mucolipins and the two- which until now have been classified as non-treatable. pore channels (TPCs) have recently been characterized Members of the transient receptor potential (TRP) cation in more detail with these novel patch-clamp techniques Christian Grimm (degree in Pharmaceutical Sciences from the University of Würzburg, Germany (2000) and Ph.D. in Pharmacology (2004), Freie Universität (FU) Berlin, Germany). After several years as Postdoctoral Research Fellow at Harvard and Stanford Universities, USA (2004–2009) and time as a Principal Scientist at Pfizer R&D in the UK (2009–2011) he is now a Senior Lecturer (Privatdozent) at the Department of Chemistry and Pharmacy, Section of Pharmacology at the University of München (LMU), Germany. His main scientific interest is on TRP cation channels and in recent years he focused on members of the TRP family that are expressed in the endolysosomal system: TRPML channels and two-pore channels (TPCs). The results of his activity have been published in more than 40 peer reviewed scientific articles, reviews and book chapters. MESSENGER 5, 30–36, 2016 31 Endolysosomal Cation Channels as Therapeutic Targets—Pharmacology of TRPML Channels Grimm (Dong et al., 2008; Dong et al., 2010; Shen et al., 2012; (Grimm et al., 2010) and against a plethora of other targets Wang et al., 2012; Zhang et al., 2012; Cang et al., 2013; (generally more than 500, each; for further information see Cheng et al., 2014; Grimm et al., 2014; Chen et al., 2014; http://pubchem.ncbi.nlm.nih.gov; AID: 1448, 1525, 1526, Jha et al., 2014; Sakurai et al., 2015; Ruas et al., 2015; Li 1562, 2719, 1809, and 2694), cross-reactivity within the et al., 2016; Zhang et al., 2016). TRPML subfamily as well as differences between human Apart from newly developed endolysosomal patch- and murine channel isoforms remained an issue. Thus, clamp techniques, it was the discovery of small molecule ML-SA1 (SF-51-type) for example is non-selective and activators (Grimm et al., 2010) that has significantly fos- potently activates all three TRPML channel isoforms while tered and facilitated TRPML channel and thus endolyso- other compounds including MK6-83 are more selective somal ion channel research in general. The availability (Grimm et al., 2010; Fig. 2(D)). In addition, some com- of small molecule TRPML channel agonists has helped pounds do show off-target effects, e.g., ML-SA1 (but to establish and to validate endolysosomal patch-clamp not SF-51) inhibits TRPC4 with an IC50 of 4.2 M techniques and to better comprehend the physiological (confirmation dose-response assay) and SF-21 (EC50 for and biophysical properties of TRPML channels includ- TRPML3 = 860 nM) activates the CRF-binding protein, ing TRPML1 and the pathophysiological consequences of albeit with a much higher EC50 (13.7 M; confirma- TRPML1 mutations in humans suffering from mucolipido- tion dose-response assay) (for further information see http://pubchem.ncbi.nlm.nih.gov; AID: 1448, 1525, 1526, MESSENGER sis type IV (Shen et al., 2012; Samie et al., 2013; Cheng et al., 2014; Wang et al., 2014; Bae et al., 2014; Chen 1562, 2719, 1809, 2694 and Grimm and Cuajungco, 2014). et al., 2014; Li et al., 2016; Zhang et al., 2016). TRPML Pharmacological inhibition of TRPML channel activity channel activators are also considered to serve as poten- has also been shown recently. Three compounds have been tial therapeutic agents for the treatment
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