Front Cover

Piezo Channels

CURRENT TOPICS IN MEMBRANES, VOLUME 79

Piezo Channels

Contents

CONTRIBUTORS

PREFACE

One - A Tour de Force: The Discovery, Properties, and Function of Piezo Channels

1. BACKGROUND

2. DISCOVERY OF PIEZO CHANNELS

2.1 Identification of Piezo genes

2.1.1 Neuro2A cell line produces mechanical current

2.1.2 Identification of Piezo1 (FAM38a)

2.1.3 Piezo1 in the plasma membrane

2.1.4 Heterologous expression

2.1.5 Inhibitors of Piezo channels

2.1.5.1 Small molecule

2.1.5.2 Peptide

2.1.5.3 Protein

2.1.6 Distribution of Piezo1 and Piezo2

2.1.7 Bilayer reconstitution of Piezo1

2.2 Piezo1 functional stoichiometry

2.3 Biophysical properties of mouse Piezo1

2.3.1 Mouse Piezo1 inactivation

2.3.2 Piezo channel clusters

2.3.3 Effects of modulating the cytoskeleton

2.3.4 Protonation of PIEZO1

2.3.5 Diseases of piezo mechanical channels

2.4 Chemical activation of Piezo1

2.5 Cytoskeleton modulates Piezo1 function

2.5.1 Tuning Piezo1 activity

2.5.2 Filamin-A modulates Piezo1 function

2.6 Cell motility and Piezo1

2.6.1 Integrin activation and Piezo1 (Fam38a)

2.6.2 Breast cancer

2.6.3 Prostate cancer

2.7 Piezo1's role in cell contact

2.7.1 Lineage choice in neural stem cells

2.7.2 Neuron–astrocyte interaction

2.7.3 Cell homeostasis

2.8 Functional role of Piezo

2.8.1 Nociception of Drosophila larvae

2.8.2 Shear stress response of Piezo1

2.8.3 Calcium influx and ATP release

2.8.4 Piezo2 and light touch

2.8.4.1 Optogenetic approach

2.8.4.2 Knockout approach

2.8.4.3 Biochemical and knockdown approach

2.9 Piezo2 channels in other roles

2.9.1 Piezo2 in foraging duck

2.9.2 Piezo2 in proprioception

2.9.3 Piezo2 channels in the gut

2.9.4 Piezo2 and pain

3. CONCLUSION

ACKNOWLEDGMENT

REFERENCES

Two - Piezo1 Channels in Vascular Development and the Sensing of Shear Stress

1. INTRODUCTION

2. SHEAR STRESS IN VASCULAR DEVELOPMENT

3. ION CHANNELS IN SHEAR STRESS SENSING

3.1 K+ channels and Cl− channels

3.2 Ca2+-permeable channels

4. PIEZO1 CHANNELS

4.1 Piezo1 channel properties

4.2 Discovery of Piezo1's role in shear stress sensing

4.3 Necessity for endothelial Piezo1 after the embryonic heart beats

4.4 Requirement for Piezo1 in endothelial cell Ca2+ entry and nonselective cationic current

4.5 The potential simplicity of Piezo1 as a stand-alone sensor

4.6 Challenges for the Piezo1 sensor hypothesis

4.7 How might activation of Piezo1 channels lead to vascular remodeling?

4.8 Mutations in human PIEZO1 gene

4.9 Relationships of Piezo1 to other candidate shear stress sensors

5. CONCLUSIONS AND FUTURE DIRECTIONS

ACKNOWLEDGMENTS

REFERENCES

Three - Origin of the Force: The Force-From-Lipids Principle Applied to Piezo Channels

1. INTRODUCTION

2. ORIGIN OF THE “FORCE-FROM-LIPIDS PRINCIPLE”

2.1 Evolutionary origins of mechanosensitive channels

2.2 Evolutionary timeline of MS channels

2.3 Piezo evolution

3. APPLICABILITY OF FORCE-FROM-LIPIDS TO EUKARYOTIC CHANNELS

3.1 Two-pore domain K+ (K2P) channels

3.2 TRPV4

3.3 Piezo1

4. WHICH FORCE IS THE RIGHT FORCE?

4.1 Membrane tension-induced gating

4.1.1 Tension-induced gating: pulling or entropy driven?

4.2 Membrane local curvature

4.2.1 Amphipaths

4.3 Role of the cytoskeleton and extracellular matrix in membrane tension-induced gating

4.4 Force-from-lipids or force-from-filament: a false dichotomy?

5. ARCHITECTURAL BLUEPRINT OF PIEZO CHANNELS

5.1 Putative molecular force-sensing domains

5.2 A Unifying structural mechanism for mechanosensitivity

6. CONCLUSIONS AND FUTURE PERSPECTIVES

REFERENCES

Four - Genetic Diseases of PIEZO1 and PIEZO2 Dysfunction

1. INTRODUCTION

2. PIEZO1 LOSS-OF-FUNCTION: CONGENITAL LYMPHATIC DYSPLASIA

3. PIEZO1 GAIN-OF-FUNCTION: HEREDITARY XEROCYTOSIS/DEHYDRATED STOMATOCYTOSIS

4. PIEZO1 LOSS-OF-FUNCTION PHENOTYPES IN ANIMAL MODELS

5. ADDITIONAL PATHOLOGICAL ASSOCIATIONS OF HUMAN PIEZO1

6. PIEZO2 LOSS-OF-FUNCTION DISEASE: RECESSIVE SYNDROME OF DISTAL ARTHROGRYPOSIS, SCOLIOSIS, MUSCLE ATROPHY, PROPRIOCEPTION DEF ...

7. PIEZO2 GAIN-OF-FUNCTION DISEASE: DOMINANT DISTAL ARTHROGRYPOSIS TYPES 3 (GORDON SYNDROME) AND 5, AND MARDEN–WALKER SYNDROME

8. PIEZO2 LOSS-OF-FUNCTION PHENOTYPES IN MOUSE MODELS

9. ADDITIONAL HUMAN GENETIC ASSOCIATIONS WITH PIEZO2

10. CONCLUSIONS AND FUTURE PROSPECTS

REFERENCES

Five - The Structural Basis for Sensing by the Piezo1 Protein

1. INTRODUCTION

1.1 Function of mechanosensitive ion channels

1.2 Identification of Piezo proteins

2. STRUCTURE OF MOUSE PIEZO1

2.1 Overall structure of mouse Piezo1

2.2 Topology of mouse Piezo1

2.3 Transmembrane skeleton of mouse Piezo1

2.4 Ion-conducting pore of mouse Piezo1

3. POSSIBLE GATING MECHANISMS OF MOUSE PIEZO1

4. CONCLUSIONS AND FUTURE PROSPECTS

REFERENCES

Six - In Touch With the Mechanosensitive Piezo Channels: Structure, Ion Permeation, and Mechanotransduction

1. INTRODUCTION

2. THE PIEZO FAMILY OF PROTEINS REPRESENTS A PHYSIOLOGICALLY AND PATHOPHYSIOLOGICALLY IMPORTANT CLASS OF MS CATION CHANNELS

2.1 Piezo1 serves as an in vivo mechanotransducer in various biological processes

2.2 Piezo2 serves as an in vivo mechanotransducer for somatosensation of mechanical force

2.3 Piezo1 and Piezo2 are linked to human genetic diseases

3. PIEZO PROTEINS FORM A DISTINCT CLASS OF MS CATION CHANNELS

3.1 Piezo-mediated MA currents display species-dependent pore properties

3.2 mPiezo1 proteins exist as oligomers

3.3 Reconstituted mPiezo1-GST fusion proteins in lipid bilayers mediate RR-sensitive cationic currents

4. THE THREE-DIMENSIONAL CRYO-EM STRUCTURE OF MPIEZO1

4.1 mPiezo1 protein purification and cryo-EM structure determination

4.2 mPiezo1 forms a three-bladed, propeller-like homotrimeric architecture

5. PIEZO1 TOPOLOGY

5.1 The C-terminal extracellular domain trimerizes to form the cap structure

5.2 The cap and blades are extracellularly located, whereas the beams and C-terminus are at the intracellular side

5.3 The anchor domain and subunit swapping

5.4 The TM topology of Piezo1 is complex and remains elusive

6. THE CENTRAL ION-CONDUCTING PORE

6.1 The mPiezo1 structure reveals a continuous central channel

6.2 Primary sequence assignment of the central pore module

6.3 Residues 2189–2547 of mPiezo1 encode the central pore module

6.4 The last putative TM forms the pore-lining IH

7. MOLECULAR BASIS FOR PIEZO ION PERMEATION, ION SELECTIVITY, AND PORE BLOCKADE

7.1 CED mediates efficient ion conduction and cation selectivity

7.2 E2495 and E2496 are the key pore determinants

7.3 The molecular basis of Piezo pore blockade

7.4 Piezo proteins are bona fide pore-forming subunits of MS cation channels

8. THE MOLECULAR BASIS FOR PIEZO MECHANOTRANSDUCTION

8.1 The mechanogating properties of Piezo channels

8.2 The flexible blade domain as force sensors?

8.3 The extended PH wing for sensing membrane tension?

8.4 The beam domains for mechanotransduction?

8.5 The N-terminal non-pore-containing region of mPiezo1 might serves as a sufficient mechanotransduction module

9. A PROPOSED WORKING MODEL FOR MECHANOSENSITIVE PIEZO CHANNELS

10. CONCLUSION AND PERSPECTIVE

ACKNOWLEDGMENTS

REFERENCES

Seven - Piezo2 in Cutaneous and Proprioceptive Mechanotransduction in VertebratesaaThis work was supported by grant ...

1. INTRODUCTION

2. SOMATOSENSORY NEURONS

2.1 Piezo2 and fast mechanoactivated current in mouse dorsal root ganglia neurons

2.2 Possible role of Piezo2 in slow mechanoactivated current

2.3 Functional regulation of Piezo2 in mouse dorsal root ganglia neurons

3. LIGHT TOUCH

3.1 Insights from mice

3.2 Insight from other vertebrates

4. PROPRIOCEPTION

5. MERKEL CELLS

6. NOCICEPTION

7. CONCLUSIONS AND PERSPECTIVES

REFERENCES

Eight - Mechanosensitive Piezo Channels in the Gastrointestinal Tract

1. THE GASTROINTESTINAL TRACT MECHANOSENSITIVITY

2. MECHANOSENSITIVE CELLS IN THE GASTROINTESTINAL TRACT

3. MECHANOSENSITIVE ION CHANNELS

3.1 Gastrointestinal epithelium mechanosensitivity

3.1.1 Static force detection by the gastrointestinal epithelium

3.1.2 Acute force detection by the gastrointestinal epithelium

3.2 Gastrointestinal smooth muscle mechanosensitivity

3.2.1 Gastrointestinal smooth muscle cell mechanosensitivity

3.2.2 Voltage-gated ion channel mechanosensitivity

3.2.3 Potassium channel mechanosensitivity

3.2.4 Nonselective cation channel mechanosensitivity

3.2.5 Interstitial cell of Cajal mechanosensitivity

3.3 Mechanosensitivity of the enteric neurons

3.3.1 Intrinsic enteric neuron mechanosensitivity

3.3.2 Extrinsic enteric neuron mechanosensitivity

3.3.3 Role of mechanosensitive ion channels in visceral mechanosensation

4. SUMMARY AND CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

Nine - Regulation of Piezo Channels by Cellular Signaling Pathways

1. INTRODUCTION

2. PHOSPHOLIPASE C AND CYCLIC ADENOSINE MONOPHOSPHATE SIGNALING

2.1 Phosphoinositide signaling

2.2 Cyclic adenosine monophosphate signaling

3. SENSITIZATION OF SENSORY ION CHANNELS BY INFLAMMATORY PATHWAYS

3.1 Piezo2 potentiation by Gq-coupled receptors

3.2 Piezo2 regulation by the cyclic adenosine monophosphate pathway

4. CALCIUM-INDUCED INHIBITION OF PIEZO CHANNELS—THE ROLE OF PHOSPHOINOSITIDES

5. CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

Ten - Role of Piezo Channels in Joint Health and Injury

1. INTRODUCTION

2. MECHANOTRANSDUCTION IN CHONDROCYTES

3. PIEZO1 AND PIEZO2 IN ARTICULAR CHONDROCYTES

4. CONTINUUM OF MECHANICAL LOADS

5. KEY CONTRIBUTORS OF PIEZO-MEDIATED HIGH-STRAIN MECHANOTRANSDUCTION IN CHONDROCYTES

5.1 Membrane-bound amplification mechanism: L-type voltage-gated Ca2+ channel

5.2 Cytoskeletal contribution: actin cytoskeleton network and dynamin GTPase

6. FOLLOW-UP QUESTIONS

7. SUMMARY

REFERENCES

Eleven - The Kinetics and the Permeation Properties of Piezo Channels

1. INTRODUCTION

2. STRUCTURE DEFINES FUNCTION: THE FORCE-SENSING AND THE PORE MODULES OF PIEZO CHANNELS

3. COMPARISON OF THE KINETICS OF PIEZO CURRENTS AGAINST THOSE OF ENDOGENOUS MECHANOSENSITIVE CHANNEL CURRENTS

4. DOMAINS INFLUENCE THE KINETICS OF PIEZO CHANNELS

5. MODELING AND ITS THERMODYNAMIC UNDERPINNINGS

6. MECHANOSENSITIVE CHANNEL GATING ENERGY; WHAT IS THE PREDICTED VALUE OF ΔG?

7. MUTATIONS IN PIEZO CHANNELS THAT AFFECT CHANNEL KINETICS

8. REMOVING PIEZO1 INACTIVATION

9. KINETIC PROPERTIES OF PIEZO1 CHANNELS ARE ALTERED BY YODA1

10. PERMEATION AND SELECTIVITY OF PIEZO CHANNELS

11. MUTATIONS THAT ALTER PORE MODULE RESIDUES AND THEIR EFFECTS ON PERMEATION AND CONDUCTANCE

12. CONCLUSIONS

ACKNOWLEDGMENT

REFERENCES

Twelve - A Microfluidic Approach for Studying Piezo Channels

1. FUNDAMENTALS OF STRESS IN SOLIDS AND FLUIDS

1.1 Active forces on a body in fluid flow

1.2 Fluid shear stress

1.3 Effect of shear stress on cell physiology

1.4 Shear application and signal collection

1.5 Shear stress calibration

2. THE SHEAR STRESS RESPONSE

2.1 Shear stress-induced Ca2+ influx via mechanosensitive ion channels

2.2 Determining shear stress thresholds

2.3 Shear stress assay for pharmacological studies

3. MECHANICAL COUPLINGS OF CYTOSKELETON TO MECHANOSENSITIVE ION CHANNELS

3.1 Cytochalasin D

3.2 Colchicine

4. SHEAR STRESS AS A HIGH-THROUGHPUT ASSAY FOR MECHANOSENSITIVE ION CHANNEL SPECIFIC DRUGS

4.1 Inhibition by peptide GsMTx4

4.2 Yoda1 activation

5. MICROFLUIDIC SHEAR STRESS CHAMBER VERSUS OTHER MECHANICAL ASSAYS

6. MICROFLUIDIC DEVICES TO MEASURE OTHER PROPERTIES OF PIEZO CHANNELS

6.1 ATP release by red blood cells

6.2 Confinement sensing

7. PERSPECTIVE AND FUTURE DEVELOPMENT

REFERENCES

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