Types of drug receptors

1
Types of drug receptors

• Practically all receptors are proteins
• Enzymes
• Ion channels
• Ligand-gated channels Ion channels that open
  upon binding of a mediator
• Voltage-gated channels Ion channels that are not
  normally controlled by ligand binding but by
  changes in the membrane potential
• Metabolic receptors hormone and
  neurotransmitter receptors that are coupled to
  biochemical secondary messenger / effector
  mechanisms

2
Physiology and pharmacology of membrane
excitation

• Excitable cell types
• Nerve cells
• Myelinated nerve fibers (fast transmission)
• Non-myelinated nerve fibers (slow transmission)
• Muscle cells
• Skeletal muscle
• Heart muscle
• Smooth muscle

striated
3
Membrane potentials and excitability

• Both excitable and non-excitable cell membranes
  have an electrical potential across their
  cytoplasmic membranes
• The membrane potential chiefly depends on the
  asymmetric distribution of sodium and potassium
  ions, and with some cells calcium ions across the
  cell membrane
• In the ground state, the orientation of the
  membrane potential is negative inside

4
How is the asymmetric distribution of ions across
the membrane maintained?
2 K
ADP Pi
ATP
3 Na
K Cl-
K
Na
5
Ionic basis of membrane potentials and
excitability

• In the resting state of excitable cells and
  throughout in the non-excitable cells the
  interior of the cell is electrically negative
  against the outside
• Electrical excitation (the action potential)
  consists in a brief, transient reversal of the
  orientation of the membrane potential
• Both the resting potential and the action
  potential are diffusion potentials

6
Diffusion potentials (1)
no potential (electroneutrality)
7
Diffusion potentials (2)
still no potential (electroneutrality)

-
8
Diffusion potentials (3)
negative
positive
-

-

-

-

-

-

-

-

-

9
Diffusion potentials (4)
Driving force 1 Entropy (equalize concentrations
on both sides)
Driving force 2 Electroneutrality (equalize
charges on both sides)
10
The Nernst equation describes the diffusion
potential at equilibrium
11
What if there are multiple diffusible ions? (1)
Intra- and extracellular cation concentrations
Actual resting membrane potential -70 mV
12
What if there are multiple diffusible ions? (2)
Goldman equation (special case for Na and K)
13
The Goldman equation and the role of ion channels
P Permeability this is where the ion channels
come in
14
The Goldman equation and the role of ion
channels (2)
change
dont change
15
The cellular resting potential is essentially a
potassium potential
negative
positive
K
16
Voltage-gated sodium channels will open upon
reversal of the resting membrane potential
negative
positive
Na
negative
positive
17
Voltage-gated sodium channels propagate the
action potential
negative
positive
-
-
-
-
Na
Na
outside
inside
Na
K
K
K
K
-
-
-
-
positive
negative
spreading action potential
18
Electrical depolarization of nerve fibers can
trigger action potentials
External stimuli of varying amplitude
time (ms)
19
The Goldman equation and the action potential
20
Planar lipid membranes allow observation of
individual channels
21
Multiple opening events of a single channel in a
planar lipid bilayer
Externally applied voltage
Multiple, successive observations
open state
base line / closed
averaged trace
Current
Time
22
Patch clamping
pipette
channel
cell
23
Cell attached mode
seal
24
Whole cell mode
suction
seal
25
Excised patch mode
seal
cell ripped apart
26
Questions

• How is the action potential initiated ?
• How is the action potential terminated ?

27
Action potential Termination (1)

• The ion flux through the voltage-gated Na
  channel is countered by a voltage-gated K
  channel that responds more slowly to
  depolarization
• Both channels spontaneously inactivate

Resulting membrane potential
Na influx
K efflux
duration a few milliseconds
28
Action potential Termination (2)
Voltage-gated channels cycle between 3
distinguishable functional states
29
Structural model of a Kv channel
Extracellular space
Cytosol
30
The KV channels opening gate is located in the
membrane
31
The KV channel in the resting state
32
The KV channel in the open state
- - -





33
The KV channel in the inactivated state
34
Action potential Initiation

• In a resting cell, an action potential can be
  initiated in a variety of ways
• By synaptic transmission. Examples Signal
  conduction from one nerve cell to another, from
  nerve cell to muscle cell
• By spontaneous, rhythmic membrane depolarization.
  Example Specialized cells in heart and smooth
  muscle
• By electrical coupling to a neighboring cell via
  gap junctions. Example Heart muscle, smooth
  muscle

35
Muscle fibers and a branching nerve ending
36
Synaptic excitation
presynaptic action potential
ENa
Firing level
EK
Presynaptic terminal
synaptic cleft
Postsynaptic terminal
37
Synaptic excitation (2)
-
Na
Na
In synapses, ligand-gated channels open upon
binding of neurotransmitters and initiate the
action potential in the post-synaptic membrane
38
Action potential initiation in heart pacemaker
cells
(negative charge left behind)
Ca
Ca
K
Ca
K
K
In heart pacemaker cells, two types of calcium
channels lead to spontaneous depolarization
39
Action potential initiation in heart pacemaker
cells
K
0 mV
CaL
-40 mV
CaT
-60 mV
slow, spontaneous prepotential
40
Cell excitation by electrical couplingacross gap
junctions

- - - - -
- - - - -

Gap junction
41
What about anions?
Opposite charge affects the Goldman equation
42
Intra- and extracellular ion concentrations

• Opening of sodium or calcium channels will
  increase the membrane potential (depolarization)
• Opening of potassium or chloride channels will
  lower the membrane potential (repolarization or
  hyperpolarization)

43
Sodium and chloride in excitatory and inhibitory
synapses
Na
positive
negative