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