This book covers the molecular structures and the cellular and in vivo function of endosomes and lysosomes, i.e. intracellular vesicles which are involved in many cellular processes such as endocytosis, intracellular trafficking, degradation of material from inside (e.g. autophagy) and outside the cell as well as exocytosis. Membranes of endolysosomal organelles contain an amazing number and diversity of ion channels. These ion channels are the topic of the present book that focusses on describing the structure, the biophysical properties, physiological functions of endolysosomal ion channels at the molecular, cellular and in vivo level.
Author(s): Christian Wahl-Schott, Martin Biel
Series: Handbook of Experimental Pharmacology, 278
Publisher: Springer
Year: 2023
Language: English
Pages: 309
City: Cham
Preface
Contents
Part I: Physiological Functions of Endolysosomal Cation Channels
NAADP-Mediated Ca2+ Signalling
1 Structure of NAADP, a Pyridine Nucleotide Ca2+ Mobilizing Molecule
2 Biosynthesis of NAADP in Cells and Tissues
3 NAADP as an Intracellular Messenger and Stimulus-Response Coupling
4 NAADP as a Messenger Regulating Ca2+ Release from Acidic Organelles
5 Properties of NAADP-Evoked Ca2+ Release Mechanisms and the Identification of NAADP-Sensitive Ion Channels
6 NAADP-Binding Proteins
7 Pharmacology of NAADP-Evoked Ca2+ Release
8 Pathophysiology of NAADP-Mediated Ca2+ Signalling
9 Conclusions
References
NAADP-Dependent TPC Current
1 Introduction
1.1 NAADP Mobilizes Ca2+ from Acidic Organelles
1.2 TPC1 and TPC2 Are Involved in NAADP-Induced Ca2+ Mobilization from Endolysosomes
1.3 Unique Properties of NAADP in Binding to Its Receptors and Releasing Ca2+
2 Interplay of NAADP and PI(3,5)P2
2.1 TPC2-Expressing Endolysosome Vacuoles Displayed Large Basal PI(3,5)P2-Dependent Currents
2.2 NAADP-Induced TPC2 Activation in Endolysosome Vacuoles with Low Basal Currents
2.3 TPC2 Is Co-dependent on Both NAADP and PI(3,5)P2 for Activation
3 Discussion
3.1 NAADP Increases the Sensitivity of TPC2 to PI(3,5)P2
3.2 NAADP Desensitizes TPC2 Currents
4 Perspectives
References
NAADP-Evoked Ca2+ Signaling: The DUOX2-HN1L/JPT2-Ryanodine Receptor 1 Axis
1 The Ca2+ Mobilizing Second Messenger NAADP: Things to Know at a Glance
2 A Novel Redox Cycle as Hub for NAADP Metabolism
3 Novel NAADP Receptors Coupling to Ca2+ Channels
4 NAADP in Immunity and Inflammation
5 Conclusion
References
TPC Functions in the Immune System
1 Introduction
1.1 Overview on Cellular Immunity
1.2 Ion Channels in Immune Cells
1.3 Endolysosomal Ion Channels
2 TPCs in Immune Cells
2.1 Physiologic Regulation of TPCs
2.2 TPCs as Pharmacological Targets
3 Two-Pore Channels in Immune Regulation
3.1 Function of TPCs in Innate Immune Cells
3.2 Function of TPCs in Adaptive Immune Cells
3.3 Modulation of TPCs in Immune Cell Signaling
4 Outlook
References
Lysosomal Ion Channels and Lysosome-Organelle Interactions
1 Lysosomal Ion Channels
1.1 H + Channels
1.2 Ca 2+ Channels
1.3 K + Channels
1.4 Na + Channels
1.5 Cl - Channels
2 Lysosome-ER Membrane Contact
2.1 Ca 2+ Transfer
2.2 Lipid Transport
2.3 Lysosomal Membrane Repair
2.4 Regulation of ER-Lysosome MCS Formation by Lysosomal Ca 2+ Release
3 Lysosome-Mitochondria Membrane Contact
3.1 Lysosome-to-Mitochondria Ca 2+ Transfer
3.2 Lysosome-Organelle MCS in Pathophysiology
4 Summary and Future Directions
References
TRPML1 and TFEB, an Intimate Affair
1 TRPMLs
2 TRPML1
3 Lysosomal Adaptation to Nutrient Availability
4 TRPML1-mTORC1-TFEB
5 TRPML1 and Lysosomal Exocytosis
6 TRPML1-TFEB and Cell Migration
7 TRPML1/TFEB and Cancer
8 TRPML1 as a Therapeutic Target for Diseases
9 Concluding Remarks
References
Lysosomal Potassium Channels
1 Introduction
2 Lysosomal Ion Homeostasis and Ion Channels
3 Potassium Channels
4 Potassium Channels in Lysosomes
4.1 BK Channel
4.1.1 Characterization of Lysosomal BK Channels
Properties and Pharmacology of Lysosomal BK Channels
Activation of Lysosomal BK Channels by TRPML1
Regulation of Lysosomal BK Channels
4.1.2 Physiological Functions of Lysosomal BK Channels
BK Channels in Lysosomal Membrane Potential
BK Channel in Lysosomal Ca2+ Signaling
BK in Lysosomal Membrane Trafficking
BK in Lysosome Functions
4.1.3 Lysosomal BK and Human Diseases
4.2 TMEM175
4.2.1 Structure of Lysosomal TMEM175
4.2.2 Characterization of Lysosomal TMEM175
4.2.3 Physiological Functions of Lysosomal TMEM175
4.2.4 Pathological Implications of Lysosomal TMEM175
4.3 Two-Pore-Domain K+ Channels
5 Conclusion and Perspectives
References
Part II: Structure and Composition of TPC and TRPML Channels
Structure and Function of Plant and Mammalian TPC Channels
1 Introduction
2 Structure and Function of Plant TPC1 from Arabidopsis thaliana
2.1 Selectivity and Gating Properties of AtTPC1
2.2 Overall Structure of AtTPC1
2.3 Pore and Selectivity Filter of AtTPC1
2.4 Voltage-Sensing Domains of AtTPC1
2.5 Ca2+ Activation Site
2.6 Luminal Ca2+ Inhibition Site
3 Mammalian TPC1 & TPC2
3.1 Selectivity and Gating Properties of Mammalian TPCs
3.2 Overall Structure of Mammalian TPCs
3.3 Ion Conduction Pore of Mammalian TPCs in Open and Closed States
3.4 Selectivity Filter of Mammalian TPCs
3.5 Voltage-Sensing Domains of Mammalian TPC
3.6 PI(3,5)P2 Binding and Channel Activation in Mammalian TPCs
References
A Structural Overview of TRPML1 and the TRPML Family
1 An Overview of TRPML Proteins
2 Expression and Purification of TRPML1 for Structure/Function Studies
2.1 The Expression and Purification of the Luminal Domain of TRPML1
2.2 The Expression and Purification of the Full-Length TRPML1
3 Structural Determination of TRPML1 by Cryo-EM
4 Structural Analysis of Endo-Lysosomal TRP Channel TRPML1
4.1 Apo-State
4.2 Agonist ML-SA1 Bound State
4.3 PIP2 Bound State
4.4 Functional Validation of TRPML
5 pH-Mediated TRPML1 Regulation
References
Endo-Lysosomal Two-Pore Channels and Their Protein Partners
1 Introduction
2 TPC-Interacting Proteins Identified by Unbiased Approaches
2.1 HCLS1-Associated Protein X-1 (HAX1)
2.2 Proteins Involved in Membrane Trafficking
3 Protein Kinases Associated with TPCs
3.1 Leucine-Rich Repeat Kinase 2 (LRRK2)
3.2 Mechanistic Target of Rapamycin (mTOR)
3.3 Citron Kinase
3.4 Other Protein Kinases
4 NAADP Receptors Associated with TPCs
4.1 JPT2
4.2 LSM12
5 Outlook
References
Part III: Tools and Methods to Characterize Endolysosomal Cation Channels
Electrophysiological Techniques on the Study of Endolysosomal Ion Channels
1 Introduction
1.1 Endolysosome System
1.2 Endolysosomal Ion Channels
2 Material and Method of Endolysosomal Patch-Clamp Technique
2.1 Enlargement of the Organelle
2.2 Isolation of the Organelle
2.3 Pipette Preparation and Recording Solutions
3 Different Protocols to Enlarge Specific Types of Endolysosome for Patch-Clamp Analysis
3.1 Whole-Endolysosome Recording
3.2 Late Endosome and Lysosome Recording
3.3 Early Endosome Recording
3.4 Recycling Endosome Recording
3.5 Other Endolysosomal Compartment Recording
3.6 Limitations and Challenges
References
The Plant Vacuole as Heterologous System to Characterize the Functional Properties of TPC Channels
1 Introduction
2 The Plant Vacuole and Channel Forming Peptides (CFPs)
3 The Plant Vacuole as Heterologous System to Express and Characterize Mammalian Endo-Lysosomal Transporters
4 The Mammalian TPCs Expressed in Mesophyll Vacuoles
4.1 The Human TPC2
4.2 The Human TPC1
5 Perspectives and Conclusions
References
Expanding the Toolbox: Novel Modulators of Endolysosomal Cation Channels
1 Introduction
2 Small-Molecule Tools for the Modulation of TRPMLs
3 Small-Molecule Tools for the Modulation of TPCs
References
Characterization of Endo-Lysosomal Cation Channels Using Calcium Imaging
1 Introduction
2 Calcium-Permeable Ion Channels in Endo-lysosomes
2.1 TPCs
2.2 TRPMLs
3 Approaches for Imaging of Lysosomal Calcium
3.1 Global Cytosolic Ca2+ Measurements
3.2 Peri-Vesicular Ca2+ Imaging
3.3 Ca2+ Imaging of Endo-Lysosomal Ca2+ Channels Redirected to the Plasma Membrane
3.4 Intra-Endo-Lysosomal Ca2+ Imaging Using Fura-Dextran or Oregon Green 488 BAPTA-1 Dextran
4 Conclusions
References
