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Types of drug receptors PowerPoint PPT Presentation

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

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Types of drug receptors

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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


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”


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


3 Na+

Na+

Ca++

Glucose

How is the asymmetric distribution of ions across the membrane maintained?

2 K+

ADP + Pi

ATP

3 Na+

K+ Cl-

K+

Na+


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


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-

-

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+

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Diffusion potentials (1)

no potential

(electroneutrality)


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-

-

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

+

+

Diffusion potentials (2)

still no potential

(electroneutrality)

+

-


-

+

Diffusion potentials (3)

negative

positive

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+

-

+

-

+

-

+

-

+

-

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Diffusion potentials (4)

Driving force 1: Entropy (equalize concentrations on both sides)

Driving force 2: Electroneutrality (equalize charges on both sides)


Cout

 ln

E =

Cin

E:

R:

T:

F:

z:

ln:

Cin, Cout

The equilibrium diffusion potential

Gas constant (8.31 J  K-1mol-1)

Absolute temperature (K)

Faraday constant (96500 Coulomb/mole)

Number of charges of single ion (1 with K+ and Na+, 2 with Ca++, -1 with Cl-)

Natural logarithm (base: e = 2.71828)

Inside and outside concentrations of the diffusible ion species

R  T

z  F

The Nernst equation describes the diffusion potential at equilibrium


Inside Outside Equilibrium potential

Na+15 mM150 mM+60 mV

K+ 150 mM6 mM-90 mV

What if there are multiple diffusible ions? (1)

Intra- and extracellular cation concentrations:

Actual resting membrane potential: -70 mV


Cout

 ln

Nernst equation:

E =

Cin

R  T

z  F

PK  [K+]out + PNa  [Na+]out

R  T

 ln

E =

PK  [K+]in + PNa  [Na+]in

F

What if there are multiple diffusible ions? (2)

Goldman equation (special case for Na and K):


PK  [K+]out + PNa  [Na+]out

R  T

 ln

E =

PK  [K+]in + PNa  [Na+]in

F

The Goldman equation and the role of ion channels

P = Permeability – this is where the ion channels come in


PK  [K+]out + PNa  [Na+]out

R  T

 ln

E =

PK  [K+]in + PNa  [Na+]in

F

The Goldman equation and the role of ion channels (2)

change

don’t change


+

+

-

K+

-

Na+

-

K+

Na+

-

-

K+

Na+

-

-

K+

Na+

-

-

Na+

-

The cellular resting potential is essentially a potassium potential

negative

positive

K+


+

+

Voltage-gated sodium channels will open upon reversal of the resting membrane potential

negative

positive

Na+

negative

positive


+

+

+

Voltage-gated sodium channels propagate the action potential

negative

positive

-

-

-

-

Na+

Na+

outside

inside

Na+

K+

K+

K+

K+

-

-

-

-

positive

negative

spreading action potential


- 55 mV

Firing level

- 70 mV

- 85 mV

Electrical depolarization of nerve fibers can trigger action potentials

External stimuli of

varying amplitude

time (ms)


ENa (+60 mV)

Repolarization:

K channels open

Na+ channels close

Depolarization:

Na channels open

(PNa > PK)

Hyperpolarization:

Na channels closed

(PK >> PNa)

Resting potential:

PK > PNa

EK (-90 mV)

The Goldman equation and the action potential


Set voltage externally

Measure resulting current

across channel

Planar lipid membranes allow observation of individual channels


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


Patch clamping

pipette

channel

cell


Cell attached mode

seal


Whole cell mode

suction

seal


Excised patch mode

seal

cell ripped apart


Questions:

  • How is the action potential initiated ?

  • How is the action potential terminated ?


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


Depolarization

Spontaneous inactivation

Closed

Open

Inactivated

Slow reactivation after membrane repolarization

Action potential: Termination (2)

Voltage-gated channels cycle between 3 distinguishable functional states


Structural model of a Kv channel

Extracellular

space

Cytosol


+ + +

- - -

+

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- - -

+ + +

K+

K+

The KV channel’s opening gate is located in the membrane


+ + +

+ + +

+

+

+

+

+

+

+

+

+

+

- - -

- - -

+

+

The KV channel in the resting state


The KV channel in the open state

- - -

+

+

+

+

+

+

+

+

+

+

+ + +

+

+


- - -

+

+

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+ + +

+

+

The KV channel in the inactivated state


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


Muscle fibers and a branching nerve ending


+

Na+

K+

presynaptic

action potential

Synaptic excitation

ENa

Firing level

EK

Presynaptic

terminal

synaptic cleft

Postsynaptic

terminal


-

-

+

Na+

+

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


+

+

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


Action potential initiation in heart pacemaker cells

K+

0 mV

Ca++L

-40 mV

Ca++T

-60 mV

slow, spontaneous prepotential


Cell excitation by electrical couplingacross gap junctions

- - - - -

+ + + +

- - - - -

+ + + +

Gap junction


negative

positive

-

+

+

-

-

+

+

-

-

+

-

+

Permeating anions leave behind

excess positive charge

Permeating cations leave behind

excess negative charge

negative

positive

R * T

PK* CK,out + PNa* CNa,out + PCl, * CCl, in

F

* ln

E =

PK* CK,in + PNa* CNa,in + PCl, * CCl, out

What about anions?

Opposite charge affects the Goldman equation:


Inside cellOutside cellEquilibrium potential

Na+15 mM150 mM+60 mV

K+ 150 mM6 mM-90 mV

Cl- 9 mM125 mM-70 mV

Ca++100 nM1.3 mM+130 mV

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)


+

Cl-

Sodium and chloride in excitatory and inhibitory synapses

Na+

positive

negative


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