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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 l.jpg

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 l.jpg

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 l.jpg

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


How is the asymmetric distribution of ions across the membrane maintained l.jpg

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 l.jpg

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


Diffusion potentials 1 l.jpg

-

-

-

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

+

+

Diffusion potentials (1)

no potential

(electroneutrality)


Diffusion potentials 2 l.jpg

-

-

-

-

-

-

-

-

-

-

+

+

+

+

+

+

+

+

+

+

Diffusion potentials (2)

still no potential

(electroneutrality)

+

-


Diffusion potentials 3 l.jpg

-

+

Diffusion potentials (3)

negative

positive

-

+

-

+

-

+

-

+

-

+

-

+

-

+

-

+

-

+


Diffusion potentials 4 l.jpg

-

-

+

+

-

-

+

+

Diffusion potentials (4)

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

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


The nernst equation describes the diffusion potential at equilibrium l.jpg

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


What if there are multiple diffusible ions 1 l.jpg

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


What if there are multiple diffusible ions 2 l.jpg

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):


The goldman equation and the role of ion channels l.jpg

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


The goldman equation and the role of ion channels 2 l.jpg

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


The cellular resting potential is essentially a potassium potential l.jpg

+

+

-

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 l.jpg

+

+

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 l.jpg

+

+

+

Voltage-gated sodium channels propagate the action potential

negative

positive

-

-

-

-

Na+

Na+

outside

inside

Na+

K+

K+

K+

K+

-

-

-

-

positive

negative

spreading action potential


Electrical depolarization of nerve fibers can trigger action potentials l.jpg

- 55 mV

Firing level

- 70 mV

- 85 mV

Electrical depolarization of nerve fibers can trigger action potentials

External stimuli of

varying amplitude

time (ms)


The goldman equation and the action potential l.jpg

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


Planar lipid membranes allow observation of individual channels l.jpg

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 l.jpg

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 l.jpg

Patch clamping

pipette

channel

cell


Cell attached mode l.jpg

Cell attached mode

seal


Whole cell mode l.jpg

Whole cell mode

suction

seal


Excised patch mode l.jpg

Excised patch mode

seal

cell ripped apart


Questions l.jpg

Questions:

  • How is the action potential initiated ?

  • How is the action potential terminated ?


Action potential termination 1 l.jpg

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


Action potential termination 2 l.jpg

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 l.jpg

Structural model of a Kv channel

Extracellular

space

Cytosol


The k v channel s opening gate is located in the membrane l.jpg

+ + +

- - -

+

+

+

+

+

+

+

+

+

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+

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+

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+

+

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- - -

+ + +

K+

K+

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


The k v channel in the resting state l.jpg

+ + +

+ + +

+

+

+

+

+

+

+

+

+

+

- - -

- - -

+

+

The KV channel in the resting state


The k v channel in the open state l.jpg

The KV channel in the open state

- - -

+

+

+

+

+

+

+

+

+

+

+ + +

+

+


The k v channel in the inactivated state l.jpg

- - -

+

+

+

+

+

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+

+

+

+

+ + +

+

+

The KV channel in the inactivated state


Action potential initiation l.jpg

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 l.jpg

Muscle fibers and a branching nerve ending


Synaptic excitation l.jpg

+

Na+

K+

presynaptic

action potential

Synaptic excitation

ENa

Firing level

EK

Presynaptic

terminal

synaptic cleft

Postsynaptic

terminal


Synaptic excitation 2 l.jpg

-

-

+

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 l.jpg

+

+

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 cells39 l.jpg

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 coupling across gap junctions l.jpg

Cell excitation by electrical couplingacross gap junctions

- - - - -

+ + + +

- - - - -

+ + + +

Gap junction


What about anions l.jpg

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:


Intra and extracellular ion concentrations l.jpg

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)


Sodium and chloride in excitatory and inhibitory synapses l.jpg

+

Cl-

Sodium and chloride in excitatory and inhibitory synapses

Na+

positive

negative


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