In the past few years, the scientific community has witnessed rapid and significant progress in the study of ion channels. Technological advance- ment in biophysics, molecular biology, and immunology has been greatly accelerated, making it possible to conduct experiments that were deemed very difficult if not impossible in the past. For example, patch-clamp tech- niques can now be used to measure ionic currents generated by almost any type of cell, thereby allowing us to analyze single-channel events. It is now possible to incorporate purified ion channel components into lipid bilayers to reconstitute an "excitable membrane." Gene cloning and monoclonal antibody techniques provide us with new approaches to the study of the molecular structure of ion channels. A variety of drugs have now been found or are suspected to interact with ion channels to exert therapeutic effects. In addition to the classical exam- ples, as represented by local anesthetics, many other drugs, including cal- cium antagonists, psychoactive drugs, cardiac drugs, and anticonvulsants, have been shown to alter the ion channel function. For certain pesticides such as pyrethroids and DDT, sodium channels are clearly the major target site. Many diseases of excitable tissues are known to be associated with, if not caused by, dysfunction of ion channels; these include cardiac ar- rhythmias, angina pectoris, cystic fibrosis, myotonia, and epilepsies, to men- tion only a few. Channel dysfunction can now be studied due to theoretical and technological developments in this area.

Table of Contents:
1 Channel Protein Engineering: An Approach to the Identification of Molecular Determinants of Function in Voltage-Gated and Ligand-Regulated Channel Proteins.- 1. The Question.- 2. The Approach.- 2.1. Channel Protein Engineering: The Strategy.- 2.2. Synthetic Channel Peptides in Lipid Bilayers.- 2.3. Single-Channel Assay: Synthetic Channel Peptides Assayed by Single-Channel Recordings in Lipid Bilayers.- 3. The Voltage-Sensitive Sodium Channel.- 3.1. Structural Model: Inferences Derived from the Primary Structure.- 3.2. The Pore Structure: Synthetic Channel Peptide.- 3.3. Single-Channel Properties: Ionic Conduction and Selectivity.- 3.4. Model of a Plausible Channel Structure.- 4. The Nicotinic Acetylcholine Receptor.- 4.1. Structural Model: Inferences Derived from the Primary Structure.- 4.2. The Pore Structure: Synthetic Channel Peptide.- 4.3. Single-Channel Properties: Ionic Conduction and Selectivity.- 4.4. Model of a Plausible Channel Structure.- 5. Other Channel Proteins.- 5.1. Calcium Channels from Mammalian Skeletal Muscle and Putative Potassium Channels from the Shaker Locus of Drosophila and Mammalian Brain.- 5.2. GABA Receptor and Glycine Receptor M2 Segment.- 5.3. The Gap Junction Channel Protein.- 6. Concluding Remarks.- 7. References.- 2 The Role of Nonprotein Domains in the Function and Synthesis of Voltage-Gated Sodium Channels.- 1. Introduction.- 1.1. Functional Properties of Sodium Channels.- 1.2. The Biochemical Approach to Channel Mechanisms.- 2. Purification and Physicochemical Characterization of Sodium Channels from Electric Organ.- 2.1. Eel Sodium Channels Are Composed of a Single Large Polypeptide.- 2.2. Physicochemical Characteristics of the Large Sodium Channel Peptide.- 3. Possible Roles of Nonprotein Domains in the Function of Sodium Channels.- 4. Functional Consequences of Manipulating Nonprotein Domains in Purified Sodium Channels.- 4.1. Removal of Sialic Acid Groups.- 4.2. Effects of Alterations in the Membrane Lipid Environment on Channel Function.- 5. Acquisition of Nonprotein Domains during Biosynthesis.- 5.1. Biosynthesis of Sodium Channels in Electrophorus Electrocytes.- 5.2. Biosynthesis of Sodium Channels in Xenopus Oocytes.- 6. Conclusion.- 7. References.- 3 The Gating Current of the Node of Ranvier.- 1. Introduction.- 2. The Charge-Voltage Relation.- 3. The Time Constants ?on and ?off.- 4. Charge Immobilization.- 5. The Chemical Nature of the Gating Particles.- 6. The Effect of Local Anesthetics.- 7. Comparison between Gating Current and Sodium Current.- 7.1. Steady-State Properties of Untreated Nodes and of Nodes Treated with Chloramine-T, Aconitine, or Batrachotoxin.- 7.2. Kinetics in Untreated Nodes and in Nodes Treated with Different Agents.- 8. References.- 4 The Inactivation of Sodium Channels in the Node of Ranvier and Its Chemical Modification.- 1. Introduction.- 2. Inactivation.- 2.1. Formal Description.- 2.2. Link with Activation.- 2.3. Kinetic Models.- 2.4. Temperature Effects.- 3. Modifiers of Both Activation and Inactivation.- 3.1. Alkaloids.- 3.2. Insecticides.- 3.3. Scorpion ?-Toxins.- 4. Modifiers of Inactivation Alone.- 4.1. Polypeptide Toxins.- 4.2. Agents of Low Molecular Weight.- 5. Modifiers as Chemical Probes of Channel Protein.- 5.1. Group-Specific Reagents.- 5.2. Modifiers and Kinetic Models.- 5.3. Modifiers and Single-Channel Studies.- 6. Summary and Conclusions.- 7. References.- 5 ATP-Activated Channels in Excitable Cells.- 1. Introduction.- 2. A Family of Nonselective Cation Channels.- 2.1. Dose-Response.- 2.2. Kinetics.- 2.3. Desensitization.- 2.4. Ion Permeation.- 2.5. Unitary Currents.- 2.6. Ligand Specificity.- 2.7. Antagonists.- 2.8. Classification of Receptor Types.- 2.9. Which Form of ATP Is Active?.- 2.10. Comparison with Other Ligand-Gated Channels.- 2.11. Comparison with Other Actions of ATP.- 2.12. Physiological Role.- 3. ATP-Activated Potassium Channels in Atrial Cells.- 4. Modulation of Voltage-Dependent and Other Channels.- 5. Summary and Conclusions.- 6. References.- 6 Regulation of the ATP-Sensitive Potassium Channel.- 1. Introduction.- 2. Regulation of the ATP-Sensitive K+ Channel by Nucleotides.- 3. The ATP-Sensitive K+ Channel Is the Receptor for Sulfonylureas.- 4. Phosphorylation of the ATP-Sensitive K+ Channel by Kinase C.- 5. Regulation of the ATP-Sensitive K+ Channel in ? Cells by Hormonal Peptides.- 6. Cardiac ATP-Sensitive K+ Channels Are Activated by Cromakalim (BRL 34915).- 7. What Are ATP-Sensitive K+ Channels Regulating?.- 8. References.- 7 Analytical Diffusion Models for Membrane Channels.- 1. Introduction.- 2. Derivation of One-Ion Channel Diffusion Theory.- 2.1. Independence.- 2.2. Nonindependence.- 3. Channel States and Transition Rates.- 3.1. Trajectories in a One-Ion Pore.- 3.2. Three-State Model.- 4. Electrodiffusion Interpretation of Transition Rates.- 4.1. Preliminaries.- 4.2. Derivations.- 5. Transition Rates as Mean First Passage Times.- 5.1. The Steady State and Mean First Passage Times.- 5.2. Mean First Passage Time.- 5.3. Mean Occupancy Times in Terms of Mean First Passage Times.- 5.4. Mean Occupancy Times and Exit Transition Rates.- 6. Standard Results.- 6.1. Binding Affinity.- 6.2. Multiple Current-Carrying Species.- 6.3. Reversal Potential.- 6.4. Block.- 7. Discussion.- 7.1. Assumptions.- 7.2. Constant-Field Diffusion Model versus Eyring Rate Theory Models.- 7.3. Future Directions.- 8. Appendix: Comparison of One-Ion Diffusion Model with Traditional Chemical Kinetics.- 9. Symbols.- 10. References.