DEPARTMENT OF ANESTHESIOLOGY, PHARMACOLOGY

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DEPARTMENT OF ANESTHESIOLOGY, PHARMACOLOGY
THERAPEUTICS, UBCPCTH 400 (Systematic
Pharmacology)Lecture 1 Structure-function of
ion channels

• Christopher A. Ahern
• University of British Columbia
• Department of Anesthesiology, Pharmacology and
  Therapeutics,
• Department of Cellular and Physiological Sciences

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Overview

• The Body Runs on Electricity
• Excitable Cells Neurons and Muscle
• The Molecular Basis for How the Electrical System
  Works The Ion Channel
• Structure-Function Relationships in Ion Channels

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The role of electrical signallingthe action
potential

• A measure of electrical potential across the cell
  membrane
• electrical signals coordinate the flow of
  information in the body muscle contraction,
  sensory perception and thought
• nervous system cognition, nociception and
  motility
• coordination of cardiac and skeletal contractions

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CELL TYPES EXPRESSING ION CHANNELS

• Neurons in the central and peripheral nervous
  systems
• caridac muscle
• skeletal muscle
• lymphocytes and pancreatic beta cells
• The transmembrane passage of ions regulates
  electrical signalling

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Life cycle of the action potential












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LIFE CYCLE OF THE ACTION POTENTIAL












More positive on the inside
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LIFE CYCLE OF THE ACTION POTENTIAL












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what generates the transmembrane potential?
extracellular
intracellular
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WHAT GENERATES THE TRANSMEMBRANE POTENTIAL?
Na 145 mM
K 5 mM
K channel
Na 5 mM
K 145 mM
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• ion channels are membrane proteins composed of
  strings of 100s /1000s of amino acids
• channels are proteins that inhabit the surface
  membrane of excitable cells in the
  cardiovascular and nervous systems
• many different types of channels expressed
  throughout the body gated by voltage and ligands
• open and close rapidly to allow the flow of their
  namesake ion sodium, potassium, calcium, etc
• ancient proteins that can be found throughout
  biology single celLed organisms, snails, us.

ION CHANNEL 101
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selective passage of ions is essential leak K
channels set up the resting potential
Na 145 mM
K
K 4 mM
extracellular
intracellular
Na 5 mM
K
K 145 mM
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The electric field of excitable tissues and
voltage-gated ion channels
Na
K
extracellular
intracellular
The push and pull of Na and K shape the action
potential
K
Na
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Voltage-gated ion channels open in response to
Changes in transmembrane potential
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quiz time.
A Cell
What is the channel?
What happens to Vm?
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Topology of voltage-gated ion channels
,CaV
KV
NaV
X 4
-Each domain has 4 alpha-helical TM
segments -S1-S4 make up the voltage-sensor -S5-S6
make up the selectivity filter
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Seeing the structure of an ion channel gives
clues to how they work
pore
voltage-sensor
voltage-sensor
outside the cell
inside the cell
40 x 10-10 meters
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selectivity
extracellular
intracellular
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SELECTIVITY
Na1 Angstrome
K1.3 Angstrome
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VOLTAGE-SENSING AND ELECTROMECHANICAL COUPLING
outside the cell
inside the cell
40 x 10-10 meters
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A VARIETY OF CHANNEL FACILITATE SIGNALLING
THROUGHOUT THE BODY

• DELAYER RECTIFIER K CHANNELS ARE SLOW TO OPEN AND
  CONTRIBUTE TO THE CARDIAC ACTION POTENTIAL
• BK LARGE CONDUCTANCE POTASSIUM CHANNELS ARE
  GATED BY CALCIUM/VOLTAGE AND CONTRIBUTE TO
  VASCULAR TONE.

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A VARIETY OF CHANNEL TYPES FACILITATE SIGNALLING
THROUGHOUT THE BODY

• DELAYER RECTIFIER K CHANNELS ARE SLOW TO OPEN AND
  CONTRIBUTE TO THE CARDIAC ACTION POTENTIAL
• BK LARGE CONDUCTANCE POTASSIUM CHANNELS ARE
  GATED BY CALCIUM/VOLTAGE AND CONTRIBUTE TO
  VASCULAR TONE.

• KATP CHANNELS CONTRIBUTE TO INSULIN SECRETION IN
  PANCREATIC BETA CELLS
• LIGAND GATED CHANNELS CONTROL SIGNALLING AT THE
  SYNAPSE

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next week Nav Pharmacology
NaV channel biophysics basics
hyper-excitability disorders epilepsy, cardiac
arrhythmia, pain
sodium channel inhibitors