Ocular Transporters in Ophthalmic Diseases and Drug Delivery (eBook)

Colin J. Barnstable, D.Phil., is Professor and Chair, Department of Neural and Behavioral Sciences Director, Penn State Hershey Neuroscience Research Institute and Co-Director, Penn State Neuroscience Institute Joyce Tombran-Tink, PhD, Department of Neural and Behavioral Sciences, Penn State Hershey Neuroscience Research Institute and Co-Director, Penn State Neuroscience Institute

Preface 6
Table of Contents 10
Contributors 14
Aquaporins and Water Transport in the Cornea 22
INTRODUCTION 22
AQUAPORIN STRUCTURE AND TRANSPORT FUNCTION 23
AQUAPORIN EXPRESSION IN OCULAR TISSUES–INDIRECT EVIDENCE FOR A ROLE IN EYE PHYSIOLOGY 23
ROLES OF AQUAPORINS IN MAMMALIAN PHYSIOLOGY DEDUCED FROM PHENOTYPES OF AQP-NULL MICE 24
OCULAR ROLES OF AQUAPORINS OUTSIDE OF THE CORNEA 26
Aquaporins and Intraocular Pressure 26
Aquaporin 1 and Cataract Formation 26
Aquaporin 4 and Retinal Signal Transduction and Edema Following Injury 27
ROLES OF AQUAPORINS IN THE CORNEA 27
Aquaporin 1 in Corneal Endothelium – its Role in Corneal Transparency 27
Aquaporins and Ocular Surface Fluid Secretion 29
Aquaporin 3 and Healing of Corneal Epithelial Wounds 30
SUMMARY AND PERSPECTIVE 32
ACKNOWLEDGMENTS 33
REFERENCES 33
Roles of Corneal Epithelial Ion Transport Mechanisms in Mediating Responses to Cytokines and Osmotic Stress 36
OVERVIEW 36
INVOLVEMENT OF ION TRANSPORT MECHANISMS IN MEDIATED RECEPTOR CONTROL OF CORNEAL EPITHELIAL CELL RENEWAL AND VOLUME REGULATION 38
ROLES OF OSMOLYTE TRANSPORTERS IN MEDIATING CONTROL OF BARRIER, DETURGESCENCE, AND EPITHELIAL CELL RENEWAL 41
Na+/K+-Adenosine Triphosphatase (ATPase) and Na:K:2Cl Cotransporter 41
K+/Cl- Cotransporter 44
Na+/H+ and Cl-/HCO - Exchangers 45
Plasma Membrane and Endoplasmic Reticulum (ER) Ca2+ Pumps 46
Organic Ion Transporters 47
ROLES OF ION CHANNELS IN MEDIATING CONTROL OF BARRIER, DETURGESCENCE, AND EPITHELIAL CELL RENEWAL 51
K+ Channels 51
Na+ Channels 52
Cl- Channels 52
Voltage-Dependent Ca2+ Channels 53
TRP Channels 56
ACKNOWLEDGEMENTS 58
REFERENCES 58
Vitamin C Transport, Delivery, and Function in the Anterior Segment of the Eye 66
INTRODUCTION 66
LENS 66
Function 66
Transport 67
CORNEA 68
Function 68
Transport 69
OCULAR SURFACE AND TEAR FILM 70
FUTURE DIRECTIONS 71
REFERENCES 72
Mechanisms of Aqueous Humor Formation 80
INTRODUCTION 80
POSSIBLE MECHANISMS FOR THE SECRETION OF AQUEOUS HUMOR 81
ION TRANSPORT BY CILIARY EPITHELIUM 82
NA+ SECRETION 82
HCO - SECRETION 85
Cl- SECRETION 87
Cl- Uptake by PE Cells 87
Na+-K+-2Cl- Symport Versus Parallel Cl-/HCO - and Na+/H+ Antiports 87
Cl- Transfer from PE to NPE Cells 89
Cl- Release from NPE Cells into the Posterior Chamber 89
Cl- REABSORPTION 91
At the Basolateral Surface of NPE Cells 91
At the Stromal Surface of PE Cells 91
REGULATION OF AQUEOUS HUMOR FORMATION 92
Cyclic AMP 92
A3 Adenosine Receptors (A3ARs) 93
Nitric Oxide 94
CONCLUSION 95
REFERENCES 95
Membrane Transporters 108
INTRODUCTION 108
LENS STRUCTURE AND FUNCTION 109
DIFFERENTIAL EXPRESSION OF MEMBRANE TRANSPORTERS IN THE LENS 110
ROLE OF MEMBRANE TRANSPORTERS IN THE NORMAL AND DIABETIC LENS 115
Diabetic Cataract: a Problem with Lens-Volume Regulation? 115
NUTRIENT TRANSPORTERS IN THE NORMAL AND CATARACTIC LENS 120
Age-Related Nuclear (ARN) Cataract - a Transport Problem? 120
Differential Expression of Nutrient Transporters in the Lens 121
Nutrient Delivery to the Lens Nucleus via the Sutures 123
A Model for Age-Related Nuclear Cataract 124
ACKNOWLEDGEMENTS 125
REFERENCES 125
Lens Na+, K+-ATPase 130
SUMMARY 130
NA, K-ATPASE DISTRIBUTION IN THE LENS 131
LENS NA, K-ATPASE TURNOVER 133
REGULATION OF LENS NA, K-ATPASE ACTIVITY 135
LENS OSMOREGULATION AND OPACIFICATION 136
ACKNOWLEDGMENTS 140
REFERENCES 140
Pathophysiology of Pericyte-containing Retinal Microvessels 146
PERICYTES AND CAPILLARY FUNCTION 146
FUNCTIONAL SPECIALIZATIONS OF THE RETINAL MICROVASCULATURE 147
DIABETES AND THE PERICYTE-CONTAINING RETINAL MICROVASCULATURE 148
EFFECTS OF DIABETES ON MICROVASCULAR KIR CHANNELS 148
THE EFFECT OF DIABETES ON P2X7 PURINOCEPTORS 150
HYPERGLYCEMIA AND PERICYTE CHANNELS 150
BREAKDOWN OF THE BLOOD–RETINAL BARRIER AND ION CHANNEL FUNCTION 151
METABOLIC MODULATION OF MICROVASCULAR FUNCTION 152
CONCLUSIONS 153
ACKNOWLEDGMENTS 153
REFERENCES 153
Molecular Mechanisms of the Inner Blood-Retinal Barrier Transporters 158
SUMMARY 158
INTRODUCTION 158
ENERGY SUPPLY AND STORAGE 160
Glucose 160
Lactate 161
Creatine 162
ANTIOXIDANT SUPPLY 162
Vitamin C 163
Cystine 163
AMINO ACID SUPPLY 165
Leucine 165
Taurine 167
ADENOSINE TRANSPORT 167
ORGANIC ANION TRANSPORT 168
ATP-BINDING CASSETTE (ABC) TRANSPORTERS 168
CONCLUSIONS 170
ACKNOWLEDGEMENTS 170
REFERENCES 170
Regulation of Transport in the RPE 176
INTRODUCTION 177
TRANSPORT OF NUTRIENTS AND IONS FROM THE SUBRETINAL SPACE TO THE CHORIOCAPILLARIS 177
MECHANISM OF TRANSPORT OF IONS IN RETINAL PIGMENT EPITHELIUM 178
THE Na+,K+-ATPase PUMP 182
K+ AND Na+ CHANNELS 182
Cl- CHANNELS 184
The ClC Family 184
Cyclic AMP-activated Cystic-Fibrosis Transmembrane Regulator (CFTR) Channels 184
CALCIUM-ACTIVATED Cl- CHANNELS 185
The Bestrophin Family 185
Calcium-Activated Cl Channels (CACL or CaCC) 185
AGONISTS ENHANCING FUNCTION OF CALCIUM-ACTIVATED Cl- CHANNELS 186
Na+/Ca2+ EXCHANGER FUNCTIONS IN RPE TO REDUCE [Ca2+]I AND ANTAGONIZES CALCIUM-ACTIVATED K+ AND Cl- CHANNELS 186
ELECTRONEUTRAL CATION-Cl- COTRANSPORTERS (SLC12) 186
REGULATION OF [Cl-]I AND THE RELATIONSHIP WITH BICARBONATE TRANSPORTERS 187
BICARBONATE TRANSPORTERS IN RETINAL PIGMENT EPITHELIUM AND FUNCTIONAL COUPLING TO OTHER RETINAL CELL LAYERS 188
BICARBONATE TRANSPORTERS CANNOT FUNCTION PROPERLY WITHOUT FUNCTIONAL CARBONIC ANHYDRASES (CAS) 189
CARBONIC ANHYDRASES 189
CARBONIC ANHYDRASE INHIBITORS OF THERAPEUTIC VALUE IN RETINAL PIGMENT EPITHELIUM-RELATED DISEASE 190
NA+/H+ (NH) ANTIPORTERS 190
MONOCARBOXYLATE TRANSPORTERS (MCT) 190
AQP1, AQP9 AND EDEMA 191
BUFFERING OF IONS IN THE SUBRETINAL SPACE IN THE LIGHT-DARK CYCLE AND EXPLANATION OF ELECTRORETINOGRAM (ERG) C-WAVE AND DELAYED HYPERPOLARIZATION 193
OTHER IMPORTANT RETINAL PIGMENT EPITHELIUM TRANSPORT MECHANISMS 194
REGULATION OF RETINAL PIGMENT EPITHELIUM TRANSPORT BY HORMONES AND AGONISTS 195
UNANSWERED QUESTIONS REGARDING RETINAL PIGMENT EPITHELIUM TRANSPORT 195
ACKNOWLEDGEMENTS 195
REFERENCES 196
Glucose Transporters in Retinal Pigment Epithelium Development 204
SUMMARY 204
INTRODUCTION 205
PROPERTIES OF GLUCOSE TRANSPORTERS 205
STRUCTURE OF THE OUTER BLOOD–RETINAL BARRIER 206
COORDINATE DEVELOPMENT OF RETINAL PIGMENT EPITHELIUM TIGHT JUNCTIONS AND TRANSCELLULAR GLUCOSE TRANSPORT 208
Development of Tight Junctions in Chick Retinal Pigment Epithelium 208
Expression of Glucose Transporters In Vivo 210
Effect of the Neural Retina on the Expression of Glucose Transporters 212
CONCLUSIONS 214
ACKNOWLEDGEMENTS 214
REFERENCES 214
Ca2+ Channels in the Retinal Pigment Epithelium 220
CALCIUM 220
Ca2+-REGULATED FUNCTIONS OF THE RETINAL PIGMENT EPITHELIUM 220
Ca2+ CHANNELS IN GENERAL 223
Ca2+ CHANNELS IN THE RETINAL PIGMENT EPITHELIUM 223
Voltage-Dependent Ca2+ Channels 223
The Functional Role of Neuroendocrine L-Type Ca2+Channels in the Retinal Pigment Epithelium 224
L-type Channels and Disease in the Retinal Pigment Epithelium 226
TRP Channels 227
Ionotropic Receptors 228
Purinergic Receptors 228
Glutamate Receptors 228
SUMMARY 228
REFERENCES 229
Taurine Transport Pathways in the Outer Retina in Relation to Aging and Disease 236
INTRODUCTION 236
TAURINE: GENERALIZED DISTRIBUTION, INTRA-RETINAL LOCALIZATION 237
FUNCTIONAL IMPORTANCE OF TAURINE IN THE RETINA 237
Mammalian Taurine Deficiency 239
TRANSPORT PATHWAYS FOR DELIVERY OF RETINAL TAURINE 239
Taurine Transport by Retinal Pigment Epithelium 241
AGEING OF THE TAURINE TRANSPORT SYSTEM: IMPLICATIONS FOR DISEASE 243
CONCLUSIONS 248
REFERENCES 249
P-Glycoprotein Expression and Function in the Retinal Pigment Epithelium 254
INTRODUCTION 254
THE RETINAL PIGMENT EPITHELIUM 254
P-GLYCOPROTEIN STRUCTURE 255
DRUG TRANSPORT 257
Mechanism of Drug Transport 257
P-GLYCOPROTEIN SUBSTRATES 257
Inhibition of P-glycoprotein 260
LOCALIZATION OF P-GLYCOPROTEIN IN THE RETINAL PIGMENT EPITHELIUM 261
OCULAR SIDE-EFFECTS OF DRUGS 262
DRUG DELIVERY 263
FUTURE DIRECTIONS 264
REFERENCES 264
The Retinal Rod NCKX1 and Cone/Ganglion Cell NCKX2 Na+/Ca2+-K+ Exchangers 276
INTRODUCTION 276
THE Na+/Ca2+-K+ EXCHANGER IN RETINAL ROD PHOTORECEPTORS 277
The Na+/Ca2+-K+ Exchanger in Rod Physiology 277
Functional and Molecular Properties of the Rod Outer Segment Na+/Ca2+-K+ Exchanger 277
Regulation of the Rod Na+/Ca2+-K+ Exchanger 278
Interaction of the Na+/Ca2+-K+ Exchanger with other ROS Proteins 279
MOLECULAR ANALYSIS OF NCKX GENE PRODUCTS 280
Cloning and Analysis of Rod NCKX1 cDNAs 280
Cloning and Analysis of a Second Retinal NCKX cDNA 281
Post-translational Modification: Alternative Splicing, N-terminal Signal-peptide Cleavage and Glycosylation of NCKX1 and NCKX2 282
Mutated Alleles of the Rod NCKX1 and Cone NCKX2 Genes in Patients with Retinal Disease 285
Na+/Ca2+-K+ EXCHANGER STRUCTURE–FUNCTION RELATIONSHIPS 285
Residues Important for Cation Transport 285
Membrane Topology and Helix Packing of the NCKX2 Protein 287
CONCLUSIONS 288
ACKNOWLEDGEMENTS 289
REFERENCES 289
Excitatory Amino Acid Transporters in the Retina 294
INTRODUCTION 294
EXCITATORY AMINO ACID TRANSPORTER (EAAT) LOCALIZATION 295
DEVELOPMENTAL EXPRESSION 298
GLUTAMATE TRANSPORTER FUNCTION 299
Role in Glutamate Clearance 299
Role in Synaptic Transmission 299
Role in Gamma Aminobutyric Acid (GABA) Synthesis 300
REGULATION OF EXCITATORY AMINO ACID TRANSPORTER FUNCTION 301
Interacting Proteins 301
Excitatory Amino Acid Transporter Trafficking 302
GLUTAMINE TRANSPORTERS 303
System A Transporters 303
System N Transporters 303
System L Transporters 304
System ASC Transporters 305
DISEASE INVOLVEMENT 305
CONCLUSIONS 306
ACKNOWLEDGEMENTS 306
REFERENCES 307
Localization and Function of Gamma Aminobutyric Acid Transporter 1 in the Retina 312
SUMMARY 312
NEUROTRANSMITTER TRANSPORTERS 313
GABA TRANSPORTERS 314
THE GABAERGIC SYSTEM IN THE RETINA 315
GABA UPTAKE AND TRANSPORTERS IN THE RETINA 317
LOCALIZATION OF GAT-1 IN THE RETINA 318
GAT-1 in Ganglion Cells and/or Displaced Amacrine Cells 318
GAT-1 in Amacrine Cells 319
GAT-1 in Bipolar Cells 322
GAT-1 in Horizontal Cells 323
GAT-1 in Müller Cells 324
Summary of the Localization of GAT-1 in the Retina 324
FUNCTIONS OF GAT-1 IN THE RETINA 325
Both GAT-1 and GAT-3 Regulate GABA Levels in the Retina 325
Regulation of GABA Receptor Activation by GAT-1 at Retinal Synapses 325
Effects of GAT-1 Blockade on Electroretinographic Responses 326
GAT-1 and Retinal Development 326
Summary of the Functions of GAT-1 in the Retina 327
ANTI-EPILEPTIC DRUGS, RETINAL GABA, AND GAT-1 327
REFERENCES 327
Biochemical Defects Associated with Genetic Mutations in the Retina-Specific ABC Transporter, ABCR, and Macular Degenerative Diseases 336
INTRODUCTION 336
MACULAR DEGENERATIONS ASSOCIATED WITH THE ABCA4 337
ABCR IS A MEMBER OF THE ATP BINDING CASSETTE (ABC) TRANSPORTER FAMILY 337
CELLULAR TRANSPORT FUNCTION IN ABCR 338
MOLECULAR GENETICS OF HUMAN ABCA4 340
PROTEIN DOMAINS OF ABCR AND THEIR FUNCTIONS 340
THE NUCLEOTIDE BINDING DOMAINS OF ABCR. 341
ABCR-RELATED DEGENERATIVE MACULOPATHIES REPRESENT COMPLEX ETIOLOGIES: POTENTIAL DIRECTIONS FOR FUTURE RESEARCH 342
ACKNOWLEDGMENTS 344
REFERENCES 344
Glutamate Transporters and Retinal Disease and Regulation 352
GLUTAMATE TRANSPORTERS 352
EAAT1 353
EAAT2 354
EAAT3 354
EAAT4 354
EAAT5 354
Other Glutamate Transporters 355
GLUTAMATE TRANSPORTERS AND RETINAL DISEASE 355
Ischemia 355
Glaucoma 357
Diabetic Retinopathy 358
Retinitis Pigmentosa 358
Leber Hereditary Optic Neuropathy 359
REGULATION OF GLUTAMATE TRANSPORT 359
Protein Kinases and Phosphatases 359
GTRAPs 361
Soluble factors 361
Transporter Substrates 363
Transporter Blockers 364
Antibiotics 364
Anesthetics 364
Other Agents 364
Conclusion 364
ACKNOWLEDGMENTS 364
REFERENCES 365
Glutamate Transport in Retinal Glial Cells during Diabetes 374
INTRODUCTION 374
THE IMPORTANCE OF GLUTAMATE TRANSPORT 375
Excitatory Amino Acid Transporters in the Retina 376
CHANGES IN GLUTAMATE HOMEOSTASIS IN THE RETINA DURING DIABETES 381
MECHANISMS INVOLVED IN ALTERED GLUTAMATE FUNCTION 384
SIGNIFICANCE OF GLUTAMATE TRANSPORTER FUNCTION 385
Neuronal Dysfunction and Cell Death 385
Reduced Threshold for Neuronal Damage Secondary to Ischemia 386
Abnormalities in Glutamate Transport as a Generalized Indicator of Müller Cell Dysfunction 386
CONCLUSION 387
ACKNOWLEDGMENTS 387
REFERENCES 387
The Emerging Significance of Drug Transporters and Metabolizing Enzymes to Ophthalmic Drug Design 394
SUMMARY 394
INTRODUCTION 394
TRANSPORTER EXPRESSION IN THE EYE 395
The Ocular Surface 395
The Back of the Eye 397
ENZYME DISTRIBUTION IN OCULAR TISSUES 398
The Cytochrome P450 Monooxygenase System 399
Cytochrome P450 Enzymes in the Eye 399
Other Oxidoreductase Systems 400
Aldehyde Oxidase 400
Ketone Reductase 400
Hydrolytic Enzymes 400
Conjugating Enzyme Systems 401
FACTORS IMPACTING OCULAR TRANSPORTERS AND METABOLIZING ENZYMES 401
Polymorphism 401
Inhibition 402
Induction 403
Excipients 404
DISEASE 404
Transporters 404
Metabolism and Ocular Disease 405
Cataract 405
Neurodegeneration 405
Ocular Lens Dislocation 406
Primary Congenital Glaucoma 406
Inflammation and Angiogenesis 406
DRUG TRANSPORTER–METABOLIC ENZYME INTERPLAY 406
CONCLUSION 409
REFERENCES 409
Barriers in Ocular Drug Delivery 418
INTRODUCTION 418
BARRIERS IN OCULAR DRUG DELIVERY 420
Anterior Segment 420
Cornea 420
Bowman’s Layer 421
Stroma 422
Descemet’s Membrane 422
Corneal Endothelium 422
Conjunctiva 422
Posterior Segment 423
Retina 424
Blood–Retinal Barrier 424
Retinal Vessels 424
Retinal Pigment Epithelium 425
PHYSICOCHEMICAL PROPERTIES OF DRUGS AFFECTING PERMEABILITY ACROSS OCULAR BARRIERS 426
EFFLUX PUMPS 427
P-Glycoprotein 428
Multi-Drug-Resistance Protein 429
STRATEGIES TO OVERCOME OCULAR BARRIERS 429
SUMMARY 429
ACKNOWLEDGEMENTS 429
REFERENCES 429
Ophthalmic Applications of Nanotechnology 434
INTRODUCTION 434
NANOSYSTEMS AND FUNDAMENTALS OF NANOTECHNOLOGY 434
Nanosystems 434
Soluble Macromolecules 435
Dendrimers 435
Micelles 437
Nanoplexes 437
Nanoparticles 438
Liposomes 438
Nanorods, Nanotubes, and Nanofibers 439
MANUFACTURING METHODS FOR NANOPARTICLES 439
NANOSURGERY 440
NANOTECHNOLOGY IN RETINAL PROSTHESES 441
Cortical Implants 441
Retinal Implants 441
NANOTECHNOLOGY IN OPHTHALMIC DIAGNOSTICS 442
In Vivo Diagnosis 442
Ex Vivo Diagnosis 443
NANOTECHNOLOGY FOR GENE DELIVERY TO THE EYE 444
NANOTECHNOLOGY FOR OCULAR DRUG DELIVERY 446
TOXICITY CONCERNS WITH NANOTECHNOLOGY 449
CONCLUSIONS 450
ACKNOWLEDGEMENTS 451
REFERENCES 451
Vitamin C Transporters in the Retina 456
CHEMISTRY AND BIOLOGIC FUNCTIONS OF ASCORBIC ACID (VITAMIN C) 456
Interconversion between Ascorbate and Dehydroascorbic Acid 458
VITAMIN C AND THE RETINA 458
DELIVERY OF VITAMIN C TO THE RETINA 459
MOLECULAR IDENTITY AND FUNCTIONAL FEATURES OF VITAMIN C TRANSPORTERS 459
Transporters for Ascorbate 459
Transporters for DHAA 460
VITAMIN C TRANSPORTERS IN THE RETINA 461
The Blood–Retinal Barrier 461
Neural Retina 463
DIABETES AND RETINAL VITAMIN C STATUS 464
POTENTIAL OF VITAMIN C TRANSPORTERS IN DRUG DELIVERY 465
CONCLUSIONS 465
REFERENCES 466
The Plasma Membrane Transporters and Channels of Corneal Endothelium 470
SUMMARY 470
INTRODUCTION 470
ELEMENTS OF THE MODEL 471
Apical Membrane: 471
Basolateral Membrane: 471
RATES OF TURNOVER 471
SYSTEM OF EQUATIONS 473
CONCLUSIONS AND PREDICTIONS FROM THE MATHEMATICAL MODEL 475
ACKNOWLEDGEMENTS 476
REFERENCES 476
Index 478