DEPARTMENT OF ANESTHESIOLOGY, PHARMACOLOGY

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DEPARTMENT OF ANESTHESIOLOGY, PHARMACOLOGY
THERAPEUTICS, UBCPCTH 400 (Systematic
Pharmacology)Lecture 2 Sodium Channel
Pharmacology I Biophysical Basics and Mechanisms
of Inhibition

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

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Overview

• sodium channels as contributors to electrical
  signalling gating
• local anesthetics
• use-dependent inhibition

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• rapidly activate and inactivate with changes in
  voltage
• contribute to the upstroke of Action potential
• 4 homologous domains, 24 tm segments. large
  membrane proteins (250 kd)
• select for Na over other cations
• 9 known isoforms NaV1.1-1.9
• no structure yet

VOLTAGE-GATED SODIUM CHANNELS DRIVE
EXCITABILITY IN THE CARDIOVASCULAR AND NERVOUS
SYSTEMS
5 ms
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SEEING THE STRUCTURE OF AN K CHANNEL GIVES
CLUES TO HOW Na CHANNELS WORK
top view
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SEEING THE STRUCTURE OF AN K CHANNEL GIVES
CLUES TO HOW Na CHANNELS WORK
pore
voltage-sensor
voltage-sensor
outside the cell
inside the cell
40 x 10-10 meters
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WHY Na CHANNEL MODULATION IS USEFUL

• Neuronal, cardiac and skeletal excitability
• arrhythmia, epilepsy and pain are due, in part,
  to excessive and unregulated electrical signaling
• Therapeutic inhibition of sodium channels can
  calm/stabilize membrane excitability

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How do Na channels contribute to electrical
signalling?
extracellular
intracellular
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How do Na contribute to electrical signalling?
Na 145 mM
Na
K 4 mM
extracellular
intracellular
Na 5 mM
K 145 mM
Na
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sodium channels drive the upstroke of the action
potential
Na
extracellular
intracellular
Na
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SODIUM CHANNEL ACTIVATION GATING
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SODIUM CHANNEL ACTIVATION GATING
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SODIUM CHANNEL ACTIVATION GATING
current-voltage relationship
INa
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SODIUM CHANNEL INACTIVATION GATING
SODIUM CHANNEL INACTIVATION GATING

• the rapid decrease in conductance controls the
  contribution to the AP
• fast inactivation is the process describing entry
  into the inactivated state
• Failure to inactivate can be lethal
• sodium channel drugs effect Na conductance by
  stabilizing the inactivated state of the channel

arrow highlights fast inactivation gating
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sodium channel function two gates define the
flow of current
Closed, Rest
inactivation gate
activation gate
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SODIUM CHANNEL INACTIVATION GATING FAST VS.
STEADY-STATE
PRE-PULSE
TEST PULSE
PRE-PULSE POTENTIAL
-100 mV
-150 mV
PEAK CURRENT TELLS YOU HOW MANY CHANNELS ARE
AVAILABLE FOR THE ACTION POTENTIAL STEADY STATE
AVAILABILITY
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sodium channel gating review

• Control the inward flux of Na
• Contribute to upstroke of the action potential
• Fast-activation and steady-state inactivation
• Fast inactivation describes the entry into the
  inactivated state, while steady-state tells you
  how many channels are already inactivated at any
  given membrane potential.
• Now, onto sodium channel inhibitors

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classes of sodium channel inhibitors

• Local anesthetics (pain)
• Anti-convulsants (epilepsy)
• Anti-arrhythmics (cardiac arrhythmias)
• Commonly referred to as a group as local
  anesthetics
• Reduce ionic conductance in a use-dependent
  manner

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Local anesthetics are amphiphilic/amphoteric
ester or amide linkage
positively charged amine (hydrophilic)
Benzene ring (hydrophobic)
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local anesthetics
aminoesters
cocaine
procaine
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local anesthetics
aminoamides
lidocaine
etidocaine
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How do LA access the LA-Receptor?The role of
charge

• the neutral base penetrates lipid membranes,
  blocks channels with low affinity
• the charged form potently inhibits the channel

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the mechanism of LA inhibitionThe role of
charge

• What is pKa?
• base is the neutral form
• lower ph will reduce LA penetration, why?
• The ability of LAs to inhibit channels is ph
  dependent

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sodium channel function two gates define the
flow of current
Closed, Rest
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AN EXAMPLE USE-DEPENDENT INHIBITION BY
LIDOCAINE MORE STIMULATIONMORE INHIBITION
-20mV
-100mV
control
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LOCAL ANESTHETICS BIND PREFERABLY TO OPEN AND
INACTIVATED CHANNELS
Closed, Rest
DRUG ENTRY (NEUTRAL)
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Drug binding stabilizes the inactivated state

• left shifting the inactivation relationship
  removes channels from the action potential
• inactivated state affinity also contributes to
  use-dependent inhibition.

CONTROL
LIDOCAINE
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Review

• Local anesthetics (LA) can be either charged or
  neutral depending on the local pH and pKa of the
  drug
• Las cross membranes in the neutral form where
  they gain access to their receptor in the channel
  on the cytoplasmic side of the membrane
• Bind preferentially to open/inactivated channels
  which leads to Use-Dependent Inhibition
• inactivated state affinity also contributes to
  use-dependent inhibition.

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Up next Nav Pharmacology II
Review of todays material
Molecular determinants of inhibition the local
anesthetic receptor
The specificity problem finding the right
channels to inhibit
hyper-excitability disorders epilepsy, cardiac
arrhythmia, pain