Title: DEPARTMENT OF ANESTHESIOLOGY, PHARMACOLOGY
1DEPARTMENT 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
2Overview
- sodium channels as contributors to electrical
signalling gating - local anesthetics
- use-dependent inhibition
3- 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
4SEEING THE STRUCTURE OF AN K CHANNEL GIVES
CLUES TO HOW Na CHANNELS WORK
top view
5SEEING 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
6WHY 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
7How do Na channels contribute to electrical
signalling?
extracellular
intracellular
8How do Na contribute to electrical signalling?
Na 145 mM
Na
K 4 mM
extracellular
intracellular
Na 5 mM
K 145 mM
Na
9sodium channels drive the upstroke of the action
potential
Na
extracellular
intracellular
Na
10SODIUM CHANNEL ACTIVATION GATING
11SODIUM CHANNEL ACTIVATION GATING
12SODIUM CHANNEL ACTIVATION GATING
current-voltage relationship
INa
13SODIUM 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
14sodium channel function two gates define the
flow of current
Closed, Rest
inactivation gate
activation gate
15SODIUM 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
16sodium 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
17classes 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
18Local anesthetics are amphiphilic/amphoteric
ester or amide linkage
positively charged amine (hydrophilic)
Benzene ring (hydrophobic)
19local anesthetics
aminoesters
cocaine
procaine
20local anesthetics
aminoamides
lidocaine
etidocaine
21How 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
22the 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
23sodium channel function two gates define the
flow of current
Closed, Rest
24AN EXAMPLE USE-DEPENDENT INHIBITION BY
LIDOCAINE MORE STIMULATIONMORE INHIBITION
-20mV
-100mV
control
25LOCAL ANESTHETICS BIND PREFERABLY TO OPEN AND
INACTIVATED CHANNELS
Closed, Rest
DRUG ENTRY (NEUTRAL)
26Drug 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
27Review
- 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.
28Up 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