Ion Channels of Excitable Membranes

by Hille, Bertil

• ISBN13: 9780878933211
• ISBN10: 0878933212
• Edition: 3rd
• Format: Hardcover
• Copyright: 2001-07-16
• Publisher: Sinauer Associates is an imprint of Oxford University Press

Summary

Ion channels underlie a broad range of the most basic biological processes, from excitation and signaling to secretion and absorption. Like enzymes, they are diverse and ubiquitous macromolecular catalysts with high substrate specificity and subject to strong regulation. This fully revised and expanded third edition of Ion Channels of Excitable Membranes describes the known channels and their physiological functions, then develops the conceptual background needed to understand their architecture and molecular mechanisms of operation. It includes new chapters on calcium signaling, structural biology, and molecular biology and genomics. Ion Channels of Excitable Membranes begins with the classical biophysical work of Hodgkin and Huxley, continues with the roles of channels in cellular signaling, then develops the physical and molecular principles needed for explaining permeation, gating, pharmacological modification, and molecular diversity, and ends with a discussion of channel evolution. Ion Channels of Excitable Membranes is written to be accessible and interesting to life scientists and physical scientists of all kinds. It introduces all the concepts that a graduate student should be aware of but is also effective in advanced undergraduate courses. It has long been the recognized authoritative overview of this field used by all neuroscientists.

Author Biography

Bertil Hille is Professor in the Department of Physiology and Biophysics at the University of Washington. He graduated summa cum laude from Yale University with a B.S. in Zoology, and earned a Ph.D. in Life Sciences at The Rockefeller University. Dr. Hille then did postdoctoral work in the laboratories of A. L. Hodgkin and R. D. Keynes. He was elected to the National Academy of Sciences in 1986, and has received numerous awards, including: the Third Annual Bristol-Myers Squibb Award for Distinguished Achievement in Neuroscience Research (1990); the Columbia University Louisa Gross Horwitz Prize for Biology or Biochemistry (1996, shared with Clay Armstrong); and the Albert Lasker Basic Medical Research Award (1999, jointly with Clay Armstrong and Roderick MacKinnon). A cell physiologist, neurobiologist, and educator, Dr. Hille works on ion channel biophysics, signaling by modulatory neurotransmitters, and intracellular calcium dynamics. The Hille laboratory has published over 140 research papers and trained fifty graduate students and postdoctoral fellows.

Table of Contents

Introduction	1	(24)
Channels and ions are needed for excitation	2	(3)
Channels get names	5	(2)
Channels have families	7	(1)
Ohm's law is central	7	(3)
The membrane as a capacitor	10	(3)
Equilibrium potentials and the Nernst equation	13	(4)
Current-voltage relations of channels	17	(4)
Ion selectivity	21	(1)
Signaling requires only small ion fluxes	21	(4)
PART I DESCRIPTION OF CHANNELS
Classical Biophysics of the Squid Giant Axon	25	(36)
The action potential is a regenerative wave of Na+ permeability increase	26	(7)
The voltage clamp measures current directly	33	(2)
The ionic current of axons has two major components: I Na and I K	35	(3)
Ionic conductances describe the permeability changes	38	(4)
Two kinetic processes control g Na	42	(3)
The Hodgkin-Huxley model describes permeability changes	45	(7)
The Hodgkin-Huxley model predicts action potentials	52	(2)
Do models have mechanistic implications?	54	(2)
Voltage-dependent gates have gating charge and gating current	56	(3)
The classical discoveries recapitualted	59	(2)
The Superfamily of Voltage-Gated Channels	61	(34)
Drugs and toxins help separate currents and identify channels	62	(2)
Drugs and toxins act at receptors	64	(5)
Gates open wide at the cytoplasmic end of the pore, and the pore narrows at the outside	69	(2)
Early evidence for a pore came from biophysics	71	(1)
There is a diversity of K channels	72	(1)
Voltage-gated Na channels are less diverse	73	(5)
Ion channels can be highly localized	78	(3)
Voltage-gated channels form a gene superfamily	81	(4)
The crystal structure shows a pore!	85	(2)
Patch clamp reveals stochastic opening of single ion channels	87	(5)
Recapitulation	92	(3)
Voltage-Gated Calcium Channels	95	(36)
Early work found Ca channels in every excitable cell	98	(2)
Ca2+ ions can regulate contraction, secretion, and gating	100	(8)
Ca2+ dependence imparts voltage dependence	108	(2)
Multiple channel types: Dihydropyridine-sensitive channels	110	(5)
Neurons have many HVA Ca-channel subtypes	115	(2)
Voltage-gated Ca channels from a homologous gene family	117	(2)
A note on Ca-channel nomenclature	119	(1)
Permeation and ionic block require binding in the pore	120	(4)
Do all Ca channels inactivate?	124	(3)
Channel opening is voltage-dependent and delayed	127	(1)
Overview of voltage-gated Ca channels	128	(3)
Potassium Channels and Chloride Channels	131	(38)
Fast delayed rectifiers keep short action potentials short	134	(1)
Slow delayed rectifiers serve other roles	134	(2)
Transient outward currents space repetitive responses	136	(4)
Shaker opens the way for cloning and mutagenesis of K channels	140	(3)
Ca2+-dependent K currents make long hyperpolarizing pauses	143	(4)
Spontaneously active cells can serve as pacemakers	147	(2)
Inward rectifiers permit long depolarizing responses	149	(4)
What are Kir channels used for?	153	(1)
The 4TM and 8TM K channels	154	(1)
The bacterial KcsA channel is much like eukaryotic K channels	155	(1)
An overview of K channels	156	(2)
A hyperpolarization-activated cation current contributes to pacemaking	158	(2)
Several strategies underlie slow rhythmicity	160	(1)
Cl channels stabilize the membrane potential	160	(2)
Cl channels have multiple functions	162	(7)
Ligand-Gated Channels of Fast Chemical Synapses	169	(32)
Ligand-gated receptors have several architectures	170	(2)
Acetylcholine communicates the message at the neuromuscular junction	172	(4)
Agonists can be applied to receptors in several ways	176	(1)
The decay of the endplate current reflects channel gating kinetics	177	(2)
Fluctuation analysis supported the Magleby-Stevens hypothesis	179	(3)
The ACh receptor binds more than one ACh molecule	182	(1)
Gaps in openings reveal slow agonist unbinding	183	(1)
Agonist usually remains bound while the channel is open	184	(1)
Ligand-gated receptors desensitize	184	(1)
An allosteric kinetic model	185	(2)
Recapitulation of nAChR channel gating	187	(1)
The nicotinic ACh receptor is a cation-permeable channel with little selectivity	187	(1)
Fast chemical synapses are diverse	188	(3)
Fast inhibitory synapses use anion-permeable channels	191	(4)
Excitatory amino acids open cation channels	195	(4)
Recapitulation of fast chemical synaptic channels	199	(2)
Modulation, Slow Synaptic Action, and Second Messengers	201	(36)
cAMP is the classic second messenger	204	(3)
cAMP-dependent phosphorylation augments ICa in the heart	207	(4)
Rundown could be related to phosphorylation	211	(1)
cAMP acts directly on some channels	211	(1)
There are many G-protein-coupled second-messenger pathways	212	(5)
ACh reveals a shortcut pathway	217	(3)
Synaptic action is modulated	220	(4)
G-protein-coupled receptors always have pleiotropic effects	224	(2)
Encoding is modulated	226	(2)
Pacemaking is modulated	228	(4)
Slow versus fast synaptic action	232	(2)
Second messengers are launched by other types of receptors	234	(2)
First overview on second messengers and modulation	236	(1)
Sensory Transduction and Excitable Cells	237	(32)
Sensory receptors make an electrical signal	237	(2)
Mechanotransduction is quick and direct	239	(9)
Visual transduction is slow	248	(2)
Vertebrate phototransduction uses cyclic GMP	250	(7)
Phototransduction in flies uses a different signaling pathway	257	(1)
Channels are complexed with other proteins	258	(1)
Chemical senses use all imaginable mechanisms	259	(2)
Pain sensation uses transduction channels	261	(2)
What is an excitable cell?	263	(6)
Calcium Dynamics, Epithelial Transport, and Intercellular Coupling	269	(40)
Intracellular organelles have ion channels	269	(5)
IP3-receptor channels respond to hormones	274	(2)
Ca-release channels can be studied in lipid bilayers	276	(2)
The ryanodine receptor of skeletal muscle has recruited a voltage sensor	278	(5)
Voltage-gated Ca channels are the voltage sensor for ryanodine receptors	283	(3)
IP3 is not the only Ca2+-mobilizing messenger	286	(1)
Intracellular stores can gate plasma-membrane Ca channels	287	(3)
The extended TRP family is diverse	290	(1)
Mitochondria clear Ca2+ from the cytoplasm by a channel	291	(1)
Protons have channels	292	(1)
Transport epithelia are vectorially constructed	293	(6)
Water moves through channels as well	299	(1)
Cells are coupled by gap junctions	300	(4)
All cells have other specialized intracellular channels	304	(1)
Recapitulation of factors controlling gating	305	(4)
PART II PRINCIPLES AND MECHANISMS OF FUNCTION
Elementary Properties of Ions in Solution	309	(38)
Early electrochemistry	310	(2)
Aqueous diffusion is just thermal agitation	312	(3)
The Nernst-Planck equation describes electrodiffusion	315	(4)
Uses of the Nernst-Planck equation	319	(2)
Brownian dynamics describes electrodiffusion as stochastic motions of particles	321	(1)
Electrodiffusion can also be described as hopping over barriers	322	(4)
Ions interact with water	326	(1)
The crystal radius is given by Pauling	326	(2)
Ion hydration energies are large	328	(3)
The ``hydration shell'' is dynamic	331	(4)
``Hydrated radius'' is a fuzzy concept	335	(3)
Activity coefficients reflect weak interactions of ions in solution	338	(4)
Equilibrium ion selectivity can arise from electrostatic interactions	342	(2)
Recapitulation of independence	344	(3)
Elementary Properties of Pores	347	(30)
Early pore theory	347	(4)
Ohm's law sets limits on the channel conductance	351	(1)
The diffusion equation also sets limits on the maximum current	352	(2)
Summary of limits from macroscopic laws	354	(1)
Dehydration rates can reduce mobility in narrow pores	355	(1)
Single-file water movements can lower mobility	356	(1)
Ion fluxes may saturate	357	(1)
Long pores may have ion flux coupling	358	(2)
Ions must overcome electrostatic barriers	360	(2)
Ions could have to overcome mechanical barriers	362	(1)
Gramicidin A is the best-studied model pore	363	(6)
Electrostatic barriers are lowered in K channels	369	(2)
A high turnover number is good evidence for a pore	371	(3)
Some carriers have pore-like properties	374	(1)
Recapitulation of pore theory	375	(2)
Counting Channels and Measuring Fluctuations	377	(28)
Neurotoxins count toxin receptors	378	(1)
Gating current counts mobile charges within the membrane	379	(4)
Digression on the amplitudes of current fluctuations	383	(2)
Fluctuation amplitudes measure the number and size of elementary units	385	(2)
A digression on microscopic kinetics	387	(6)
The patch clamp measures single-channel currents directly	393	(3)
Summary of single-channel conductance measurements	396	(4)
Thoughts on the conductance of channels	400	(2)
Channels are not crowded	402	(3)
Structure of Channel Proteins	405	(36)
The nicotinic ACh receptor is a pentameric glycoprotein	406	(1)
Complete amino acid sequences were determined by cloning	407	(4)
Ligand-gated receptors form a large homologous family	411	(3)
Determining topology requires chemistry	414	(5)
Electron microscopy shows a tall hourglass	419	(2)
A partial crystal structure shows a pentameric ring	421	(2)
Voltage-gated channels also became a gene superfamily	423	(4)
Are K channels tetramers?	427	(1)
Auxiliary subunits change channel function	428	(5)
KcsA is a teepee	433	(1)
Electron paramagnetic resonance probes structure	434	(1)
Kv channels have a lot of mass hanging as a layer cake in the cytoplasm	435	(2)
Excitatory GluRs combine parts of two bacterial proteins	437	(3)
Is there a pattern?	440	(1)
Selective Permeability: Independence	441	(30)
Partitioning into the membrane can control permeation	442	(3)
The Goldman-Hodgkin-Katz equations describe a partitioning-electrodiffusion model	445	(4)
Uses of the Goldman-Hodgkin-Katz equations	449	(1)
Derivation of the Goldman-Hodgkin-Katz equations	450	(3)
A more generally applicable voltage equation	453	(1)
Voltage-gated channels have high ion selectivity	454	(6)
Other channels have low ion selectivity	460	(2)
Ion channels act as molecular sieves	462	(7)
Selectivity filters can be dynamic	469	(1)
First recapitulation of selective permeability	469	(2)
Selective Permeability: Saturation and Binding	471	(32)
Ionic currents do not obey the predictions of independence	471	(7)
Simple models for one-ion channels	478	(5)
Na channel permeation can be described by state models	483	(3)
Some channels must hold more than one ion at a time	486	(3)
Single-file multi-ion models	489	(5)
Multi-ion pores can select by binding	494	(3)
Anion channels have complex transport properties	497	(2)
Recapitulation of selective permeation	499	(1)
What do permeation models mean?	500	(3)
Classical Mechanisms of Block	503	(36)
Affinity and time scale of the drug-receptor reaction	504	(2)
Binding in the pore can make voltage-dependent block: Protons	506	(5)
Some blocking ions must wait for gates to open: Internal TEA	511	(5)
Local anesthetics give use-dependent block	516	(4)
Local anesthetics alter gating kinetics	520	(4)
Antiarrhythmic action	524	(1)
State-dependent block of ligand-gated receptors	525	(2)
Multi-ion channels may show multi-ion block	527	(6)
STX and TTX are the most potent and selective blockers of Na channels	533	(2)
Some scorpion toxins plug K channel pores	535	(1)
Recapitulation of blocking mechanisms	536	(3)
Structure-Function Studies of Permeation and Block	539	(36)
Charges in the M2 segment help nAChR channels conduct	540	(5)
What can a charged residue do?	545	(3)
Channel blockers interact with M2 and M1 segments	548	(3)
Cysteine substitution can test accessibility of residues	551	(2)
The S5-S6 linker forms the outer funnel and pore in K channels	553	(5)
The S5-S6 linker forms the outer funnel and pore in Na channels	558	(3)
Divalent/monovalent selectivity depends on charge density and electrostatics	561	(3)
The S6/M2 segment contributes to the inner pore	564	(2)
Inward rectification is voltage-dependent block	566	(6)
Functions are not independent	572	(1)
Recapitulation of structure-function studies	573	(2)
Gating Mechanisms: Kinetic Thinking	575	(28)
First recapitulation of gating	575	(2)
Proteins change conformation during activity	577	(4)
Events in proteins occur across the frequency spectrum	581	(2)
Topics in classical kinetics	583	(6)
Additional kinetic measures are essential	589	(5)
Most gating charge moves in significant steps	594	(1)
A new round of kinetic models for Shaker K channel gating	594	(3)
For BK channels we need three-dimensional kinetic models	597	(2)
Nav and Cav channels require more complex models	599	(1)
Channels can have several open states	600	(2)
Conclusion of channel gating kinetics	602	(1)
Gating: Voltage Sensing and Inactivation	603	(32)
Simple equilibrium principles of voltage sensing and charge movement	603	(2)
Early mutagenesis points to the S4 segment	605	(3)
The S4 segment does carry much of the gating charge	608	(4)
Several residues in S4 move fully across the membrane	612	(3)
Movements around S4 are observed optically	615	(2)
Recapitulation of voltage sensing	617	(1)
What is a gate?	617	(3)
Pronase clips inactivation gates	620	(2)
Inactivation is coupled to activation	622	(2)
Microscopic inactivation can be rapid and voltage-independent	624	(4)
Fast inactivation gates are tethered plugs	628	(3)
Fast inactivation of Na channels involves a cytoplasmic loop	631	(1)
Slow inactivation is distinct from fast inactivation: A new gate?	632	(2)
Recapitulation of inactivation gating	634	(1)
Modification of Gating in Voltage-Sensitive Channels	635	(28)
Many peptide toxins slow inactivation	636	(5)
A group of lipid-soluble toxins changes many properties of Na channels	641	(4)
Reactive reagents eliminate inactivation of Na channels	645	(1)
External Ca2+ ions shift voltage-dependent gating	646	(5)
Surface-potential calculations	651	(6)
Much of the negative charge is on the channel	657	(1)
Surface-potential theory has shortcomings	658	(2)
Recapitulation of gating modifiers	660	(1)
What are models for?	661	(2)
Cell Biology and Channels	663	(30)
Channel genes can be identified by classical genetics	664	(3)
Expression of channels is dynamic during development	667	(2)
Transcription of nAChR genes is regulated by activity, position, and cell type	669	(4)
Channel mRNA can be alternatively spliced and edited	673	(3)
Channel synthesis and assembly occurs on membranes	676	(3)
Sequences on channel subunits are used for quality control	679	(1)
Membrane proteins can be localized and immobilized	680	(2)
nACh receptors become clustered and immobilized	682	(5)
Multivalent PDZ proteins cluster channels at glutamatergic synapses	687	(1)
Channels are sorted and move in vesicles	687	(4)
Recapitulation	691	(2)
Evolution and Origins	693	(30)
Channels of lower animals resemble those of higher animals	699	(2)
Channels are prevalent in eukaryotes and prokaryotes	701	(4)
Channels mediate sensory-motor responses	705	(4)
Channel evolution is slow	709	(4)
Gene duplication and divergence create families of genes	713	(3)
Proteins are mosaics	716	(3)
Speculations on channel evolution	719	(3)
Conclusion	722	(1)
References	723	(65)
Index	788