TABLE OF CONTENTS CHAPTER 1. EQUILIBRIUM THERMODYNAMICS. Introduction 1.1 Chemical Potentials and Activities 1.1.1 Thermodynamic Preliminaries. The Electrochemical Potential 1.1.2 The Interphase Equilibrium Condition 1.1.3 Electrochemical Potentials in Terms of Measurable Solution Variables: Introduction, and the Effect of Electrostatic Potential 1.1.4 The Gibbs-Duhem Equation 1.1.5 Dependence of the Chemical Potential on Pressure 1.1.6 Dependence of the Chemical Potential on Composition 1.1.7 Units 1.1.8 Activity and Activity Coefficient 1.2 Ion Equilibrium across Membranes 1.2.1 The Nernst Equilibrium 1.2.2 Origin of the Nernst Potential 1.2.3 Specific Ion Electrodes 1.2.4 Activity Coefficient Considerations 1.2.5 The Donnan Equilibrium 1.3 Chemical Equilibrium Problems CHAPTER 2. FREE DIFFUSION. Introduction 2.1 Free Diffusion of Nonelectrolytes 2.1.1 The Teorell Equation 2.1.2 Integration of the Teorell Equation; Fick's First Law; Solute Permeability 2.1.3 Unstirred Layers 2.1.4 Applications of Solution Theory 2.1.5 Fick's Second Law and Convective Diffusion 2.1.6 Justification of the Steady-State Assumption: Time Scales in Biological Transport 2.2 Free Diffusion of Electrolytes 2.2.1 Differences between Electrolyte and Nonelectrolyte Diffusion 2.2.2 The Electrodiffusion Equation 2.2.3 Integration of the Electrodiffusion Equation 2.2.4 Some Special Cases Equilibrium Uniform Composition Diffusion Potential of a Bi-Ionic System Active and Passive Exchange with a Closed Compartment Equal Total Concentrations on the Two Sides of the Membrane: The Constant-Field Equation 2.2.5 Ionic Permeability and the Resting Potential of the Cell 2.2.6 Charged Membranes 2.2.7 Limitations of the Electrodiffusion Equation and Its Solutions Problems CHAPTER 3. THE CELL. Introduction 1 3.1 Overview 3.2 The Structure of an Animal Cell 3.2.1 Composition and Structure of the Plasma Membrane Heterogeneity of Cell Membranes The Mosaic Model of the Plasma Membrane The Glycocalyx and Surface Charge 3.2.2 The Internal Structure of the Cell 3.3 Metabolism: The Production of ATP 3.4 Intracellular Transport 3.4.1 Intracellular Diffusion 3.4.2 Protein Transport Transport into the Nucleus Transport into the Mitochondrion 3.4.3 Vesicular Transport Endocytosis Exocytosis, Secretion and Transcytosis 3.5 Cellular Motility and Locomotion 3.5.1 Actin-Based Movement and Chemotaxis 3.5.2 Cilia and Flagella Problems CHAPTER 4. FACILITATED DIFFUSION: CHANNELS AND CARRIERS. Introduction 4.1 Mechanisms of Channels and Carriers 4.1.1 Hallmarks of Mediated Transport 4.1.2 Ion Selectivity of Channels 4.1.3 Energetics of Ion Selectivity, and Steric Effects 4.1.4 Ion Selectivity of Channels: Summary 4.1.5 The Structure of Ion Channels: Selectivity Filters, Gates, and Energy Profiles 4.1.6 Regulation of the Gating Process 4.1.7 Classification of Ion Channels. Aquaporins and Gap Junctions 4.1.8 Carrier Models 4.1.9 Carriers and Channels: Convergences and Differences 4.2 Kinetics of Facilitated Transport 4.2.1 Models of Ion Channel Transport: Overview 4.2.2 Energy Barrier and Binding Models of Channel Transport Ionic Independence: Absolute Rate Theory Saturable Channels: Kinetic Analysis 4.2.3 The Patch Clamp and Two Applications Acetylcholine Receptor Channel Kinetics Voltage and Current Sensitivity of a Voltage-Activated Sodium Channel 4.2.4 Stochastic Properties of Channels: Membrane Noise Analysis 4.2.5 The Simplest Model of Carrier Transport: Assumptions 4.2.6 The Simplest Model of Carrier Transport: Equations 4.2.7 Monosaccharide Transport in the Erythrocyte 4.2.8 More Complex Carrier Models 4.2.9 Exchangers and Cotransporters 4.3 Inhibition of Facilitated Transport 2 4.3.1 Inhibition of Channel Transport: Channel Block 4.3.2 Inhibition of Carrier Transport Problems CHAPTER 5. ACTIVE TRANSPORT. Introduction 5.1 Active Transport: General Considerations 5.1.1 Metabolic Coupling and Affinity 5.1.2 Classification of Active Transport Processes 5.1.3 Identification of Active Transport Processes 5.2 Mechanisms of Active Transport 5.2.1 Scalar Active Transport: Overview 5.2.2 Primary Scalar Transport 5.2.3 Secondary Scalar Transport Cotransport Countertransport 5.2.4 Vectorial Active Transport, the Curie Theorem and Substrate Activation 5.2.5 Sodium-Potassium Exchange 5.2.6 Pump Selectivity and Other Properties Shared with Passive Carriers 5.3 Kinetics of Active Transport 5.3.1 A Simple Secondary Scalar Transport Model: Assumptions 5.3.2 A Simple Secondary Scalar Transport Model: Equations 5.3.3 More Complex Symport Models; the Sodium-Glucose Transporter 5.3.4 Primary Scalar Transport 5.3.5 Flux Equations for Primary Scalar Transport 5.3.6 Relation between the Coupling Parameter Γ and the Affinity of the Metabolic Reaction 5.3.7 Vectorial Active Transport and the Nature of Na-K Exchange 5.3.8 Pumps and Leaks Problems CHAPTER 6. NONEQUILIBRIUM THERMODYNAMICS. Introduction 6.1 The Basic Phenomenological Equations 6.1.1 Conjugate Forces and Fluxes 6.1.2 Phenomenological Coefficients and Linear Thermodynamics 6.1.3 Frictional Interpretation of the Phenomenological Equations 6.1.4 A Cautionary Note before Proceeding 6.2 Nonequilibrium Thermodynamic Description of Passive Transport 6.2.1 Setting the Stage 6.2.2 The Chemical Potential of the Solvent 6.2.3 A New Set of Forces and Fluxes; Osmotic Pressure 6.2.4 The Kedem-Katchalsky Equations 6.2.5 Physical Significance of the Reflection Coefficient: Semipermeable Membranes and the Osmometer, Steric Effects and Sieving 6.2.6 Osmotic Pressure of Solutions; Donnan Osmotic Pressure; Osmotic Effects on Cells 6.2.7 Passive Transport of Multiple Nonelectrolytes 6.2.8 Passive Transport of Electrolytes: Electrokinetic Phenomena 3 . 6.3 Nonequilibrium Thermodynamic Description of Active Transport 6.3.1 Definition of Active Transport 6.3.2 Coupling between Nonconjugate Forces and Fluxes 6.3.3 Nonequilibrium Thermodynamics of Motor Proteins and ATP Synthase 6.4 Limitations of Nonequilibrium Thermodynamics 6.4.1 Closeness to Equilibrium: A Limitation Intrinsic to Linearized Nonequilibrium Thermodynamics 6.4.2 The Concentration Dependence of the Phenomenological Coefficients 6.4.3 Closeness to Equilibrium in Biological Systems 6.4.4 The Information Content of Nonequilibrium Thermodynamics 6.4.5 Approximations in the Derivation of the Kedem-Katchalsky Equations Problems CHAPTER 7. MODELS OF TRANSPORT ACROSS CELL MEMBRANES. Introduction 7.1 Transport Across the Lipid Bilayer of Cell Membranes 7.1.1 Evidence for Nonelectrolyte Diffusion Across the Lipid Bilayer 7.1.2 A Simple Model of Transbilayer Diffusion 7.1.3 Potential Barriers in the Bilayer 7.2 Models of Transport Through Pores 7.2.1 Classification of Pore Transport Models 7.2.2 Hydraulic Conductivity of a Pore 7.2.3 Hindered Diffusion; Solute Permeability as a Probe of Pore Radius 7.2.4 Other Factors Affecting Estimated Pore Size; The Equivalent Pore 7.2.5 Hindered Convection (Sieving); the Reflection Coefficient as a Probe of Pore Radius 7.2.6 Combined Diffusion and Convection through Pores 7.2.7 Single-File Transport through Pores 7.2.8 The Permeability Ratio of Larger Pores 7.3 Electrical Analogs 7.3.1 Equivalent Circuit for the Passive Flux of a Single Ion 7.3.2 Equivalent Circuit for the Passive Transport of Multiple Ions 7.3.3 The Electrical Analog of a Rheogenic Pump 7.3.4 Some Final Remarks Problems CHAPTER 8. REGULATION AND FEEDBACK. Introduction 8.1 Regulation of Transport 8.1.1 Receptor-Mediated Second Messenger Systems: Cyclic AMP and Antidiuretic Hormone 8.1.2 Direct Hormonal Regulation without an Extracellular Receptor: Aldosterone 8.1.3 Calcium-Based Regulation Maintenance of a Low Cytosolic Calcium Concentration Calcium Signaling Calcium Handling in Cells and Compartmental Analysis 8.2 Feedback in Transport Systems: Insulin 8.3 Regulation by Transport 8.3.1 Regulation of Cell Volume 4 8.3.2 Regulation of Cell pH Problems Appendix 8.1 Nonequilibrium Binding in Compartmental Analysis CHAPTER 9. EXCITABLE CELLS. Introduction 9.1 Nerve 9.1.1. The Resting Neuron 9.1.2. The Action Potential: Electrical Aspects The Membrane Action Potential: Resting State Hodgkin and Huxley's Equations for the Dependence of Conductance on Membrane Potential Excitation of the Membrane Action Potential The Propagating Action Potential: Cable Theory The Role of Myelin 9.1.3. The Action Potential: Molecular Aspects Hodgkin and Huxley's Channel Model More Recent Models of the Potassium and Sodium Channels of Nerve 9.1.4. Synaptic Transmission 9.2 Muscle 9.2.1. The Resting Muscle Fiber 9.2.2. Excitation and Excitation-Contraction Coupling Neuromuscular Transmission and Excitation: the Acetylcholine Receptor Excitation-Contraction Coupling 9.2.3. Molecular Mechanisms of Muscle Contraction Problems CHAPTER 10. EPITHELIAL TRANSPORT. Introduction 10.1 Organization of Epithelial and Endothelial Cell Layers and Some Consequences 10.1.1 The Organization of Epithelial and Endothelial Cell Layers 10.1.2 The Pathways across Leaky and Tight Epithelia 10.1.3 Transport in a Parallel Path System 10.1.4 Coupling of Transepithelial Water Flow to Active Ion Transport The Curran Model The Standing Gradient Model The Sodium Recirculation Model The Cotransporter Hypothesis 10.1.5 The Effect of Unstirred Layers on Transepithelial Diffusion and Osmosis: Concentration Polarization 10.1.6 Electrical Analogs of Cell Layers 10.2 Examples of Epithelial and Endothelial Function 10.2.1 Absorption Absorption of Sugars in the Small Intestine Transport of Water and Sodium in the Proximal Tubule of the Kidney Transport of Water and Sodium in the Distal Tubule of the Kidney 10.2.2 Secretion 10.2.3 Filtration Problems Appendix 10.1 Convection, Diffusion and Mass Addition in Channel Geometries 5 CHAPTER 11. GAS TRANSPORT. Introduction 11.1 Partial Pressure and the Equations for Gas Flux 11.2 Overview of the Gas Transport Process 11.3 Gas Exchange in the Lung 11.4 Oxygen Transport in the Blood 11.5 Transport from Red Blood Cells to Tissue 11.5.1 Reaction-Diffusion Processes 11.5.2 The Krogh Tissue Cylinder 11.5.3 Modifications to the Basic Krogh Model 11.5.4 Beyond the Krogh Cylinder Problems 6