Download - 66aa1Legand Gated Ion Channel

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Phar 590/735 - Winter 2006Dr. Jane IshmaelOffice: Phar 411Phone: 737-5783

E mail: [email protected].

SIGNAL TRANSDUCTION

THE LIGAND-GATED ION CHANNELS

1. BACKGROUND

Three Types of Transmembrane Channel:

1. Ligand-gated

Ligand binds to ion channel alters ion conductance

2. Voltage-gated

Change in transmembrane voltage gradient alters ion

conductance3. Second messenger regulated

Binding of a ligand to a G-protein coupled receptor generates a second messenger that regulates ionconductance of a channel


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Neurons communicate with each other at synapses

Neurons signal by transmitting electrical signals (action potentials)along their axons (0.1 mm to 3 m)

Action potentials are initiated at the initial segment of the axon and

are conducted down the axon at rates of 1 100m / sec Many axons are insulated by a myelin sheath to increase the

speed of transmission (many are not insulated)


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Electrical signals flow in onedirection (action potential ispropagated unidirectionally) and make specificconnectionswith postsynaptic target cells (i.e networks are not random)

At the end of the axon, voltage changes trigger the release ofneurotransmitters

Drug selectivity is based on the fact that different neuronalpathways utilize different neurotransmitters

It has been estimated that one neuron communicates with 1000others!


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ION CHANNELS MEDIATE FASTSIGNALLING EVENTS

Speeds of around one millisecond

G PROTEIN-COUPLED RECEPTORS (GPCR) use mechanisms thatare at least one hundred times slower

TRANSMEMBRANE RECEPTORS WITH CYTOSOLIC DOMAINS

100s millisecs to minutes

STEROID/HORMONE FAMILY of NUCLEAR RECEPTORS

Respond in minutes to hours

Note that in many casesMORE THAN ONE TYPE of RECEPTOR has evolved to

recognize a specific ligand/neurotransmitter

e.g GABA, glutamate, serotonin, acetylcholine use GPCRs andligand-gated ion channels


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2 BASIC CHARACTERISTICS of ligand-activated channels

LIGAND GATED = NEUROTRANSMITTER ACTIVATED

Ligand-gated ion channels are transmembraneproteins.

Comprised of multiple subunits that assemble in themembrane to form a central pore.

WHEN NEUROTRANSMITTER binds the PROTEINundergoes a CONFORMATIONAL CHANGE

The CONFORMATIONAL CHANGE OPENS a POREACROSS the PLASMA MEMBRANE

The STRUCTURE of the protein determines whichIONS flow into or out of the cell through the poreresulting in:

o EXCITATION or

o INHIBITION

A conformational change INACTIVATES the CHANNEL

Further conformational change resets the channel to aCLOSED state i.e. ready to be activated


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3 THERE ARE SEVERAL SUPERFAMILIES OFLIGAND-GATED IN CHANNELS

4 CYS-LOOP SUPERFAMILY

5 subunitsmake 1 receptor

Each subunit has 4 transmembrane domains


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Two distinct groups:

4.1 CATIONIC RECEPTORS

Nicotinic Acetylcholine Receptors

5-HT3Receptors

4.2 ANIONIC RECEPTORS

GABAA

Glycine

4.3 Nicotinic Acetylcholine Receptor

REVIEW pages 71 to 75 (Chapter 6) of the required,Principles of Pharmacology Text.

Mediates fast neurotransmission at the neuromuscular junction,peripheral autonomic ganglia and the CNS


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4.4 GABA and Glycine-activated channels

GABA(g-aminobutyric acid) andGlycineare inhibitory

neurotransmitters

GABA is the major inhibitory neurotransmitter inbrain Glycine is the major inhibitory neurotransmitter inspinal cord

and brainstem(trace amounts of GABA are found in theperiphery).

Antagonists of inhibitory neurotransmitters cause convulsions

4.4.1 GABAAreceptor

Heterooligomeric protein, composed of 5 subunits that span the

cell membrane to form a chloridechannel Multiple subtypes of each subunit

GABA binds to the extracellular surface channel opens

allowing Cl_ions flow down their concentration gradient

hyperpolarization of postsynaptic neuronal membrane


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4.4.2 Glycine Receptor

High concentrations in the spinal cord and brain stem

Inhibitoryneurotransmitter

Chloride channel Oligomeric transmembrane protein comprised of 5 subunits

Strychnine is a competitive glycine antagonist (powerfulconvulsant)

Strychnine-sensitive inhibitory glycine receptor

5. Glutamate Receptors

Major excitatory neurotransmitter in the brain.

25-30% of neurons utilize glutamate as a neurotransmitter.

4 subunits make 1 receptor

membrane topology is distinct from subunits of the cys loop family

Ionotropic Glutamate receptors

Metabotropic glutamate receptors are GPCR

Originally classified pharmacologically based upon activation bysynthetic glutamate analogues:

(1) NMDA (N-methyl-D-aspartate)

(2) non-NMDA:

All 3 types of ionotropic glutamate receptor are composed ofmultiple subunits that assemble to form a central cationchannel.

Each subunit is encoded by its own gene.


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COOH

IN

OUT

H2N

Membrane Topology of Glutamate Receptor Subunit

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