Ion Channels of Excitable Membranes

ISBN-10: 0878933212

ISBN-13: 9780878933211

Edition: 3rd 2001

Authors: Bertil Hille

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This fully revised and expanded third edition describes the known channels and their physiological functions, then develops the conceptual background needed to understand their architecture and molecular mechanisms of operation.
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Book details

List price: $89.95
Edition: 3rd
Copyright year: 2001
Publisher: Sinauer Associates, Incorporated
Binding: Hardcover
Pages: 814
Size: 7.25" wide x 9.50" long x 1.25" tall
Weight: 3.608
Language: English

Channels and ions are needed for excitation
Channels get names
Channels have families
Ohm's law is central
The membrane as a capacitor
Equilibrium potentials and the Nernst equation
Current-voltage relations of channels
Ion selectivity
Signaling requires only small ion fluxes
Description of Channels
Classical Biophysics of the Squid Giant Axon
The action potential is a regenerative wave of Na[superscript +] permeability increase
The voltage clamp measures current directly
The ionic current of axons has two major components: I[subscript Na] and I[subscript K]
Ionic conductances describe the permeability changes
Two kinetic processes control g[subscript Na]
The Hodgkin-Huxley model describes permeability changes
The Hodgkin-Huxley model predicts action potentials
Do models have mechanistic implications?
Voltage-dependent gates have gating charge and gating current
The classical discoveries recapitulated
The Superfamily of Voltage-Gated Channels
Drugs and toxins help separate currents and identify channels
Drugs and toxins act at receptors
Gates open wide at the cytoplasmic end of the pore, and the pore narrows at the outside
Early evidence for a pore came from biophysics
There is a diversity of K channels
Voltage-gated Na channels are less diverse
Ion channels can be highly localized
Voltage-gated channels form a gene superfamily
The crystal structure shows a pore!
Patch clamp reveals stochastic opening of single ion channels
Voltage-Gated Calcium Channels
Early work found Ca channels in every excitable cell
Ca[superscript 2+] ions can regulate contraction, secretion, and gating
Ca[superscript 2+] dependence imparts voltage dependence
Multiple channel types: Dihydropyridine-sensitive channels
Neurons have many HVA Ca-channel subtypes
Voltage-gated Ca channels form a homologous gene family
A note on Ca-channel nomenclature
Permeation and ionic block require binding in the pore
Do all Ca channels inactivate?
Channel opening is voltage-dependent and delayed
Overview of voltage-gated Ca channels
Potassium Channels and Chloride Channels
Fast delayed rectifiers keep short action potentials short
Slow delayed rectifiers serve other roles
Transient outward currents space repetitive responses
Shaker opens the way for cloning and mutagenesis of K channels
Ca[superscript 2+]-dependent K currents make long hyperpolarizing pauses
Spontaneously active cells can serve as pacemakers
Inward rectifiers permit long depolarizing responses
What are K[subscript ir] channels used for?
The 4TM and 8TM K channels
The bacterial KcsA channel is much like eukaryotic K channels
An overview of K channels
A hyperpolarization-activated cation current contributes to pacemaking
Several strategies underlie slow rhythmicity
Cl channels stabilize the membrane potential
Cl channels have multiple functions
Ligand-Gated Channels of Fast Chemical Synapses
Ligand-gated receptors have several architectures
Acetylcholine communicates the message at the neuromuscular junction
Agonists can be applied to receptors in several ways
The decay of the endplate current reflects channel gating kinetics
Fluctuation analysis supported the Magleby-Stevens hypothesis
The ACh receptor binds more than one ACh molecule
Gaps in openings reveal slow agonist unbinding
Agonist usually remains bound while the channel is open
Ligand-gated receptors desensitize
An allosteric kinetic model
Recapitulation of nAChR channel gating
The nicotinic ACh receptor is a cation-permeable channel with little selectivity
Fast chemical synapses are diverse
Fast inhibitory synapses use anion-permeable channels
Excitatory amino acids open cation channels
Recapitulation of fast chemical synaptic channels
Modulation, Slow Synaptic Action, and Second Messengers
cAMP is the classic second messenger
cAMP-dependent phosphorylation augments I[subscript Ca] in the heart
Rundown could be related to phosphorylation
cAMP acts directly on some channels
There are many G-protein-coupled second-messenger pathways
ACh reveals a shortcut pathway
Synaptic action is modulated
G-protein-coupled receptors always have pleiotropic effects
Encoding is modulated
Pacemaking is modulated
Slow versus fast synaptic action
Second messengers are launched by other types of receptors
First overview on second messengers and modulation
Sensory Transduction and Excitable Cells
Sensory receptors make an electrical signal
Mechanotransduction is quick and direct
Visual transduction is slow
Vertebrate phototransduction uses cyclic GMP
Phototransduction in flies uses a different signaling pathway
Channels are complexed with other proteins
Chemical senses use all imaginable mechanisms
Pain sensation uses transduction channels
What is an excitable cell?
Calcium Dynamics, Epithelial Transport, and Intercellular Coupling
Intracellular organelles have ion channels
IP[subscript 3]-receptor channels respond to hormones
Ca-release channels can be studied in lipid bilayers
The ryanodine receptor of skeletal muscle has recruited a voltage sensor
Voltage-gated Ca channels are the voltage sensor for ryanodine receptors
IP[subscript 3] is not the only Ca[superscript 2+]-mobilizing messenger
Intracellular stores can gate plasma-membrane Ca channels
The extended TRP family is diverse
Mitochondria clear Ca2+ from the cytoplasm by a channel
Protons have channels
Transport epithelia are vectorially constructed
Water moves through channels as well
Cells are coupled by gap junctions
All cells have other specialized intracellular channels
Recapitulation of factors controlling gating
Principles and Mechanisms of Function
Elementary Properties of Ions in Solution
Early electrochemistry
Aqueous diffusion is just thermal agitation
The Nernst-Planck equation describes electrodiffusion
Uses of the Nernst-Planck equation
Brownian dynamics describes electrodiffusion as stochastic motions of particles
Electrodiffusion can also be described as hopping over barriers
Ions interact with water
The crystal radius is given by Pauling
Ion hydration energies are large
The "hydration shell" is dynamic
"Hydrated radius" is a fuzzy concept
Activity coefficients reflect weak interactions of ions in solution
Equilibrium ion selectivity can arise from electrostatic interactions
Recapitulation of independence
Elementary Properties of Pores
Early pore theory
Ohm's law sets limits on the channel conductance
The diffusion equation also sets limits on the maximum current
Summary of limits from macroscopic laws
Dehydration rates can reduce mobility in narrow pores
Single-file water movements can lower mobility
Ion fluxes may saturate
Long pores may have ion flux coupling
Ions must overcome electrostatic barriers
Ions could have to overcome mechanical barriers
Gramicidin A is the best-studied model pore
Electrostatic barriers are lowered in K channels
A high turnover number is good evidence for a pore
Some carriers have pore-like properties
Recapitulation of pore theory
Counting Channels and Measuring Fluctuations
Neurotoxins count toxin receptors
Gating current counts mobile charges within the membrane
Digression on the amplitudes of current fluctuations
Fluctuation amplitudes measure the number and size of elementary units
A digression on microscopic kinetics
The patch clamp measures single-channel currents directly
Summary of single-channel conductance measurements
Thoughts on the conductance of channels
Channels are not crowded
Structure of Channel Proteins
The nicotinic ACh receptor is a pentameric glycoprotein
Complete amino acid sequences were determined by cloning
Ligand-gated receptors form a large homologous family
Determining topology requires chemistry
Electron microscopy shows a tall hourglass
A partial crystal structure shows a pentameric ring
Voltage-gated channels also became a gene superfamily
Are K channels tetramers?
Auxiliary subunits change channel function
KcsA is a teepee
Electron paramagnetic resonance probes structure
Kv channels have a lot of mass hanging as a layer cake in the cytoplasm
Excitatory GluRs combine parts of two bacterial proteins
Is there a pattern?
Selective Permeability: Independence
Partitioning into the membrane can control permeation
The Goldman-Hodgkin-Katz equations describe a partitioning-electrodiffusion model
Uses of the Goldman-Hodgkin-Katz equations
Derivation of the Goldman-Hodgkin-Katz equations
A more generally applicable voltage equation
Voltage-gated channels have high ion selectivity
Other channels have low ion selectivity
Ion channels act as molecular sieves
Selectivity filters can be dynamic
First recapitulation of selective permeability
Selective Permeability: Saturation and Binding
Ionic currents do not obey the predictions of independence
Simple models for one-ion channels
Na channel permeation can be described by state models
Some channels must hold more than one ion at a time
Single-file multi-ion models
Multi-ion pores can select by binding
Anion channels have complex transport properties
Recapitulation of selective permeation
What do permeation models mean?
Classical Mechanisms of Block
Affinity and time scale of the drug-receptor reaction
Binding in the pore can make voltage-dependent block: Protons
Some blocking ions must wait for gates to open: Internal TEA
Local anesthetics give use-dependent block
Local anesthetics alter gating kinetics
Antiarrhythmic action
State-dependent block of ligand-gated receptors
Multi-ion channels may show multi-ion block
STX and TTX are the most potent and selective blockers of Na channels
Some scorpion toxins plug K channel pores
Recapitulation of blocking mechanisms
Structure-Function Studies of Permeation and Block
Charges in the M2 segment help nAChR channels conduct
What can a charged residue do?
Channel blockers interact with M2 and M1 segments
Cysteine substitution can test accessibility of residues
The S5-S6 linker forms the outer funnel and pore in K channels
The S5-S6 linker forms the outer funnel and pore in Na channels
Divalent/monovalent selectivity depends on charge density and electrostatics
The S6/M2 segment contributes to the inner pore
Inward rectification is voltage-dependent block
Functions are not independent
Recapitulation of structure-function studies
Gating Mechanisms: Kinetic Thinking
First recapitulation of gating
Proteins change conformation during activity
Events in proteins occur across the frequency spectrum
Topics in classical kinetics
Additional kinetic measures are essential
Most gating charge moves in significant steps
A new round of kinetic models for Shaker K channel gating
For BK channels we need three-dimensional kinetic models
Na[subscript v] and Ca[subscript v] channels require more complex models
Channels can have several open states
Conclusion of channel gating kinetics
Gating: Voltage Sensing and Inactivation
Simple equilibrium principles of voltage sensing and charge movement
Early mutagenesis points to the S4 segment
The S4 segment does carry much of the gating charge
Several residues in S4 move fully across the membrane
Movements around S4 are observed optically
Recapitulation of voltage sensing
What is a gate?
Pronase clips inactivation gates
Inactivation is coupled to activation
Microscopic inactivation can be rapid and voltage-independent
Fast inactivation gates are tethered plugs
Fast inactivation of Na channels involves a cytoplasmic loop
Slow inactivation is distinct from fast inactivation: A new gate?
Recapitulation of inactivation gating
Modification of Gating in Voltage-Sensitive Channels
Many peptide toxins slow inactivation
A group of lipid-soluble toxins changes many properties of Na channels
Reactive reagents eliminate inactivation of Na channels
External Ca[superscript 2+] ions shift voltage-dependent gating
Surface-potential calculations
Much of the negative charge is on the channel
Surface-potential theory has shortcomings
Recapitulation of gating modifiers
What are models for?
Cell Biology and Channels
Channel genes can be identified by classical genetics
Expression of channels is dynamic during development
Transcription of nAChR genes is regulated by activity, position, and cell type
Channel mRNA can be alternatively spliced and edited
Channel synthesis and assembly occurs on membranes
Sequences on channel subunits are used for quality control
Membrane proteins can be localized and immobilized
nACh receptors become clustered and immobilized
Multivalent PDZ proteins cluster channels at glutamatergic synapses
Channels are sorted and move in vesicles
Evolution and Origins
Channels of lower animals resemble those of higher animals
Channels are prevalent in eukaryotes and prokaryotes
Channels mediate sensory-motor responses
Channel evolution is slow
Gene duplication and divergence create families of genes
Proteins are mosaics
Speculations on channel evolution
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