66aa1legand gated ion channel

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

    E mail: Jane.Ishmael@oregonstate.edu.

    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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