Transport of ions and small molecules across membranes

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Chapter 2

• Transport of ions and small molecules across
  membranes
• By
• Stephan E. Lehnart Andrew R. Marks

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2.1 Introduction

• Cell membranes define compartments of different
  compositions.
• The lipid bilayer of biological membranes has a
  very low permeability for most biological
  molecules and ions.

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2.1 Introduction

• Most solutes cross cell membranes through
  transport proteins.
• The transport of ions and other solutes across
  cellular membranes controls
• electrical functions
• metabolic functions

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2.2 Channels and carriers are the main types of
membrane transport proteins

• There are two principal types of membrane
  transport proteins
• Channels
• Carriers

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2.2 Channels and carriers are the main types of
membrane transport proteins

• Ion channels catalyze the rapid and selective
  transport of ions down their electrochemical
  gradients.
• Transporters and pumps are carrier proteins.
• They use energy to transport solutes against
  their electrochemical gradients.
• In a given cell, several different membrane
  transport proteins work as an integrated system.

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2.3 Hydration of ions influences their flux
through transmembrane pores

• Salts dissolved in water form hydrated ions.
• The hydrophobicity of lipid bilayers is a barrier
  to movement of hydrated ions across cell
  membranes.

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2.3 Hydration of ions influences their flux
through transmembrane pores

• By catalyzing the partial dehydration of ions,
  ion channels allow for the rapid and selective
  transport of ions across membranes.
• Dehydration of ions costs energy, whereas
  hydration of ions frees energy.

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2.4 Electrochemical gradients across the cell
membrane generate the membrane potential

• The membrane potential across a cell membrane is
  due to
• an electrochemical gradient across a membrane
• a membrane that is selectively permeable to ions

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2.4 Electrochemical gradients across the cell
membrane generate the membrane potential

• The Nernst equation is used to calculate the
  membrane potential as a function of ion
  concentrations.
• E equilibrium potential (volts)
• R the gas constant (2 cal mol1 K1)
• T absolute temperature (K 37C 307.5 K)
• z the ions valence (electric charge)
• F Faradays constant (2.3 104 cal volt1
  mol1)
• XA concentration of free ion X in
  compartment A
• XB concentration of free ion X in
  compartment B

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2.4 Electrochemical gradients across the cell
membrane generate the membrane potential

• Cells maintain a negative resting membrane
  potential with the inside of the cell slightly
  more negative than the outside.
• The membrane potential is a prerequisite for
  electrical signals and for directed ion movement
  across cellular membranes.

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2.5 K channels catalyze selective and rapid ion
permeation

• K channels function as water-filled pores that
  catalyze the selective and rapid transport of K
  ions.
• A K channel is a complex of four identical
  subunits, each of which contributes to the pore.

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2.5 K channels catalyze selective and rapid ion
permeation

• The selectivity filter of K channels is an
  evolutionarily conserved structure.
• The K channel selectivity filter catalyzes
  dehydration of ions, which
• confers specificity
• speeds up ion permeation

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2.6 Different K channels use a similar gate
coupled to different activating or inactivating
mechanisms

• Gating is an essential property of ion channels.
• Different gating mechanisms define functional
  classes of K channels.

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2.6 Different K channels use a similar gate
coupled to different activating or inactivating
mechanisms.

• The K channel gate is distinct from the
  selectivity filter.
• K channels are regulated by the membrane
  potential.

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2.7 Voltage-dependent Na channels are activated
by membrane depolarization and translate
electrical signals

• The inwardly directed Na gradient maintained by
  the Na/K-ATPase is required for the function of
  Na channels.

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2.7 Voltage-dependent Na channels are activated
by membrane depolarization and translate
electrical signals

• Electrical signals at the cell membrane activate
  voltage-dependent Na channels.
• The pore of voltage-dependent Na channels is
  formed by one subunit, but its overall
  architecture is similar to that of 6TM/1P K
  channels.
• Voltage-dependent Na channels are inactivated by
  specific hydrophobic residues that block the pore.

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2.8 Epithelial Na channels regulate Na
homeostasis

• The epithelial Na channel/degenerin family of
  ion channels is diverse.
• The epithelial Na channels and Na/K-ATPase
  function together to direct Na transport through
  epithelial cell layers.
• The ENaC selectivity filter is similar to the K
  channel selectivity filter.

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2.9 Plasma membrane Ca2 channels activate
intracellular functions

• Cell surface Ca2 channels translate membrane
  signals into intracellular Ca2 signals.

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2.9 Plasma membrane Ca2 channels activate
intracellular functions

• Voltage-dependent Ca2 channels are asymmetric
  protein complexes of five different subunits.
• The a1 subunit of voltage-dependent Ca2 channels
  forms the pore and contains pore loop structures
  similar to K channels.

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2.9 Plasma membrane Ca2 channels activate
intracellular functions

• The Ca2 channel selectivity filter forms an
  electrostatic trap.
• Ca2 channels are stabilized in the closed state
  by channel blockers.

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2.10 Cl channels serve diverse biological
functions

• Cl channels are anion channels that serve a
  variety of physiological functions.
• Cl channels use an antiparallel subunit
  architecture to establish selectivity.

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2.10 Cl channels serve diverse biological
functions

• Selective conduction and gating are structurally
  coupled in Cl channels.
• K channels and Cl channels use different
  mechanisms of gating and selectivity.

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2.11 Selective water transport occurs through
aquaporin channels

• Aquaporins allow rapid and selective water
  transport across cell membranes.
• Aquaporins are tetramers of four identical
  subunits, with each subunit forming a pore.

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2.11 Selective water transport occurs through
aquaporin channels

• The aquaporin selectivity filter has three major
  features that confer a high degree of selectivity
  for water
• size restriction
• electrostatic repulsion
• water dipole orientation

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2.12 Action potentials are electrical signals
that depend on several types of ion channels

• Action potentials enable rapid communication
  between cells.
• Na, K, and Ca2 currents are key elements of
  action potentials.
• Membrane depolarization is mediated by the flow
  of Na ions into cells through voltage-dependent
  Na channels.

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2.12 Action potentials are electrical signals
that depend on several types of ion channels

• Repolarization is shaped by transport of K ions
  through several different types of K channels.
• The electrical activity of organs can be measured
  as the sum of action potential vectors.
• Alterations of the action potential can
  predispose for arrhythmias or epilepsy.

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2.13 Cardiac and skeletal muscles are activated
by excitation-contraction coupling

• The process of excitation-contraction coupling,
  which is initiated by membrane depolarization,
  controls muscle contraction.
• Ryanodine receptors and inositol
  1,4,5-trisphosphate receptors are Ca2 channels.
• Ca2 ions are released from intracellular stores
  into the cytosol through them.

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2.13 Cardiac and skeletal muscles are activated
by excitation-contraction coupling

• Intracellular Ca2 release through ryanodine
  receptors in the sarcoplasmic reticulum membrane
  stimulates contraction of the myofilaments.
• Several different types of Ca2 transport
  proteins, including the Na/Ca2-exchanger and
  Ca2-ATPase are important for
• decreasing the cytosolic Ca2 concentration
• controlling muscle relaxation

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2.14 Some glucose transporters are uniporters

• To cross the blood-brain barrier, glucose is
  transported across endothelial cells of small
  blood vessels into astrocytes.

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2.14 Some glucose transporters are uniporters

• Glucose transporters are uniporters that
  transport glucose down its concentration
  gradient.
• Glucose transporters undergo conformational
  changes that result in a reorientation of their
  substrate binding sites across membranes.

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2.15 Symporters and antiporters mediate coupled
transport

• Bacterial lactose permease functions as a
  symporter.
• It couples lactose and proton transport across
  the cytoplasmic membrane.
• Lactose permease uses the electrochemical H
  gradient to drive lactose accumulation inside
  cells.
• Lactose permease can also use lactose gradients
  to create proton gradients across the cytoplasmic
  membrane.

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2.15 Symporters and antiporters mediate coupled
transport

• The mechanism of transport by lactose permease
  likely involves inward and outward
  configurations.
• They allow substrates to
• bind on one side of the membrane and to
• be released on the other side
• The bacterial glycerol-3-phosphate transporter is
  an antiporter that is structurally related to
  lactose permease.

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2.16 The transmembrane Na gradient is essential
for the function of many transporters

• The plasma membrane Na gradient is maintained by
  the action of the Na/K-ATPase.
• The energy released by movement of Na down its
  electrochemical gradient is coupled to the
  transport of a variety of substrates.
• The Na/Ca2-exchanger is the major transport
  mechanism for removal of Ca2 from the cytosol of
  excitable cells.

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2.16 The transmembrane Na gradient is essential
for the function of many transporters

• The gastrointestinal tract absorbs sugar through
  the Na/glucose transporter.
• The Na/K/Cl-cotransporter regulates
  intracellular Cl concentrations.
• Na/Mg2-exchangers transport Mg2 out of cells.

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2.17 Some Na transporters regulate cytosolic or
extracellular pH

• Na/H exchange controls intracellular acid and
  cell volume homeostasis.
• The net effect of Na/HCO3-cotransporters is to
  remove acid by directed transport of HCO3.

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2.18 The Ca2-ATPase pumps Ca2 into
intracellular storage compartments

• Ca2-ATPases undergo a reaction cycle involving
  two major conformations, similar to that of
  Na/K-ATPases.
• Phosphorylation of Ca2-ATPase subunits drives
• conformational changes
• translocation of Ca2 ions across the membrane

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2.19 The Na/K-ATPase maintains the plasma
membrane Na and K gradients

• The Na/K-ATPase is a P-type ATPase that is
  similar to the Ca2-ATPase and the H-ATPase.
• The Na/K-ATPase maintains the Na and K
  gradients across the plasma membrane.
• The plasma membrane Na/K-ATPase is
  electrogenic
• it transports three Na ions out of the cell for
  every two K ions it transports into the cell.

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2.19 The Na/K-ATPase maintains the plasma
membrane Na and K gradients

• The reaction cycle for Na/K-ATPase is described
  by the Post-Albers scheme.
• It proposes that the enzyme cycles between two
  fundamental conformations.

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2.20 The F1Fo-ATP synthase couples H movement to
ATP synthesis or hydrolysis

• The F1Fo-ATP synthase is a key enzyme in
  oxidative phosphorylation.
• The F1Fo-ATP synthase is a multisubunit molecular
  motor.
• It couples the energy released by movement of
  protons down their electrochemical gradient to
  ATP synthesis.

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2.21 H-ATPases transport protons out of the
cytosol

• Proton concentrations affect many cellular
  functions.
• Intracellular compartments are acidified by the
  action of V-ATPases.
• V-ATPases are proton pumps that consist of
  multiple subunits, with a structure similar to
  F1Fo-ATP synthases.

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2.21 H-ATPases transport protons out of the
cytosol

• V-ATPases in the plasma membrane serve
  specialized functions in
• acidification of extracellular fluids
• regulation of cytosolic pH

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Supplement Most K channels undergo rectification

• Inward rectification occurs through
  voltage-dependent blocking of the pore.

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Supplement Mutations in an anion channel cause
cystic fibrosis

• Cystic fibrosis is caused by mutations in the
  gene encoding the CFTR channel.
• CFTR is an anion channel that can transport
  either Cl or HCO3.
• Defective secretory function in cystic fibrosis
  affects numerous organs.