Download signal transduction the ligand-gated ion channels

Phar 590/735 - Winter 2006
Dr. Jane Ishmael
Office: Phar 411
Phone: 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
conductance
3. Second messenger regulated
Binding of a ligand to a G-protein coupled receptor –
generates a second messenger that regulates ion
conductance of a channel
1
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)
2
Electrical signals flow in one direction (action potential is
propagated unidirectionally) and make specific connections
with postsynaptic target cells (i.e networks are not random)
• At the end of the axon, voltage changes trigger the release of
neurotransmitters
• Drug selectivity is based on the fact that different neuronal
pathways utilize different neurotransmitters
• It has been estimated that one neuron communicates with 1000
others!
3
ION CHANNELS MEDIATE FAST SIGNALLING EVENTS
Speeds of around one millisecond
G PROTEIN-COUPLED RECEPTORS (GPCR) use mechanisms that
are 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 cases
MORE THAN ONE TYPE of RECEPTOR has evolved to
recognize a specific ligand/neurotransmitter
e.g GABA, glutamate, serotonin, acetylcholine use GPCRs and
ligand-gated ion channels
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2
BASIC CHARACTERISTICS of ligandactivated channels
LIGAND GATED = NEUROTRANSMITTER ACTIVATED
• Ligand-gated ion channels are transmembrane
proteins.
• Comprised of multiple subunits that assemble in the
membrane to form a central pore.
• WHEN NEUROTRANSMITTER binds the PROTEIN
undergoes a CONFORMATIONAL CHANGE
• The CONFORMATIONAL CHANGE OPENS a PORE
ACROSS the PLASMA MEMBRANE
• The STRUCTURE of the protein determines which
IONS flow into or out of the cell through the pore
resulting in:
o EXCITATION or
o INHIBITION
• A conformational change INACTIVATES the CHANNEL
• Further conformational change “resets” the channel to a
CLOSED state i.e. ready to be activated
5
3
THERE ARE SEVERAL SUPERFAMILIES OF
LIGAND-GATED IN CHANNELS
4
CYS-LOOP SUPERFAMILY
5 subunits make 1 receptor
Each subunit has 4 transmembrane domains
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Two distinct groups:
4.1 CATIONIC RECEPTORS
• Nicotinic Acetylcholine Receptors
• 5-HT3 Receptors
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) and Glycine are inhibitory
neurotransmitters
•
•
GABA is the major inhibitory neurotransmitter in brain
•
Antagonists of inhibitory neurotransmitters cause convulsions
Glycine is the major inhibitory neurotransmitter in spinal cord
and brainstem (trace amounts of GABA are found in the
periphery).
4.4.1
GABAA receptor
• Heterooligomeric protein, composed of 5 subunits that span the
cell membrane to form a chloride channel
• Multiple subtypes of each subunit
• GABA binds to the extracellular surface fi channel opens
allowing Cl_ ions flow down their concentration gradient fi
hyperpolarization of postsynaptic neuronal membrane
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4.4.2
Glycine Receptor
• High concentrations in the spinal cord and brain stem
• Inhibitory neurotransmitter
• Chloride channel
• Oligomeric transmembrane protein comprised of 5 subunits
• Strychnine is a competitive glycine antagonist (powerful
convulsant)
• 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 by
synthetic glutamate analogues:
(1) NMDA (N-methyl-D-aspartate)
(2) non-NMDA:
• All 3 types of ionotropic glutamate receptor are composed of
multiple subunits that assemble to form a central cation channel.
• Each subunit is encoded by its own gene.
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Membrane Topology of Glutamate Receptor Subunits
H2N
OUT
IN
COOH
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