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DEPARTMENT OF ANESTHESIOLOGY, PHARMACOLOGY

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Title: DEPARTMENT OF ANESTHESIOLOGY, PHARMACOLOGY


1
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

2
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

3
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

4
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

5
Life cycle of the action potential












6
LIFE CYCLE OF THE ACTION POTENTIAL












More positive on the inside
7
LIFE CYCLE OF THE ACTION POTENTIAL












8
what generates the transmembrane potential?
extracellular
intracellular
9
WHAT GENERATES THE TRANSMEMBRANE POTENTIAL?
Na 145 mM
K 5 mM
K channel
Na 5 mM
K 145 mM
10
  • 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
11
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
12
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
13
Voltage-gated ion channels open in response to
Changes in transmembrane potential
14
quiz time.
A Cell
What is the channel?
What happens to Vm?
15
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
16
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
17
selectivity
extracellular
intracellular
18
SELECTIVITY
Na1 Angstrome
K1.3 Angstrome
19
VOLTAGE-SENSING AND ELECTROMECHANICAL COUPLING
outside the cell
inside the cell
40 x 10-10 meters
20
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.

21
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

22
next week Nav Pharmacology
NaV channel biophysics basics
hyper-excitability disorders epilepsy, cardiac
arrhythmia, pain
sodium channel inhibitors
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