biology for engineers: cellular and systems neurophysiology
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Biology for Engineers: Cellular and Systems Neurophysiology. Christopher Fiorillo BiS 521, Fall 2009 042 350 4326, [email protected]. Part 5: Neurotransmitters, Receptors, and Signal Transduction Reading: Bear, Connors, and Paradiso Chapter 6. Neurotransmitters. - PowerPoint PPT PresentationTRANSCRIPT
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Biology for Engineers: Cellular and Systems Neurophysiology
Christopher Fiorillo
BiS 521, Fall 2009
042 350 4326, [email protected]
Part 5: Neurotransmitters, Receptors, and Signal Transduction
Reading: Bear, Connors, and Paradiso
Chapter 6
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Neurotransmitters• Conventional transmitters
– The basic excitatory and inhibitory transmitters• Glutamate, GABA, glycine
– Modulatory transmitters• acetylcholine, norepinephrine, dopamine, serotonin, histamine
– Peptides• Many types, example: endorphin
• Unconventional transmitters– Membrane permeable; not released from vesicles– May not have specific, dedicated receptors– Examples:
• Endocannabinoids• Nitric Oxide• Retrograde transmission• These may sometimes be referred to as “inter-cellular messengers” rather
than “neurotransmitters”
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Distribution of Major Modulatory Neurotransmitters
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Peptide Neurotransmitters• Peptides are often cotransmitters: they are released together with a
small transmitter• Release of peptides typically requires a high-frequency train of
stimuli• Peptides act on slow metabotropic receptors. There are not
peptide-gated ion channels• There are a great divesity of peptides
– Examples:• Opioid peptides
– Endorphin, enkephalin, dynorphin
• Substance P• Orexin
• The functions of peptides are generally not well understood– They can have excitatory or inhibitory effects– They are best thought of as modulatory
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Synthesis of Neurotransmitters• Each neurotransmitter has its own specific
synthetic enzyme or enzymes
• In some cases, the synthetic enzyme is found exclusively in neurons that release that neurotransmitter– Thus it serves as a marker for those
neurons
– Example: Tyrosine hydroxylase for norepinephrine and dopamine containing neurons
• In other cases, the enzymes are found in all cells, but are expressed at higher levels in neurons that use that neurotransmitter– Example: glutamate
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Receptor Pharmacology• Ligands are molecules that bind to a receptor
– Natural or artificial
• Agonists bind and activate a receptor• Antagonists bind to a receptor and prevent its activation
by agonists
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Major Receptor Classifications for Major Neurotransmitters
• Glutamate– AMPA, NMDA, kainate– mGluR1 - mGluR8
• GABA– GABAA
– GABAB
• Norepinephrine– Alpha1, Alpha2, Beta
• Dopamine– D1 - D5
• Serotonin (5-HT)– 5-HT3
– 5-HT1 5-HT2 5-HT4 5-HT5
• Acetylcholine– Nicotinic– Muscarinic (M1 - M5)
Ionotropic, ligand-gated ion channelsMetabotropic, G-protein coupled receptors
• These are only major divisions. Finer distinctions have been made.
• All of the ionotropic receptors have multiple types of subunits, and different types of subunits combine to make a receptor / ion channel.
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Ligand-gated ion channels• Most are pentamers
– Glutamate receptors are tetramers
• Most require two transmitter molecules to bind in order to open the channel
• Some have binding sites for modulators– GABAA is modified by several commonly used classes of drugs
– These drugs enhance the effect of GABA, and reduce anxiety
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Ionotropic Receptors (Ligand-gated Ion Channels)
• Fast kinetics (a few ms)• Excitatory or inhibitory,
depending on the channel’s ion selectivity
• Most common types:– Glutamate-gated
• Cation channels (permable to both Na+ and K+)
• Excitatory
– GABA-gated• Cl- channels
• Inhibitory
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Glutamate EPSCs
Fast Excitatory and Inhibitory Postsynaptic Potentials• Mediated by Ionotropic Receptors (ligand-gated ion channels)
• Fast GABA IPSPs (~30 ms) typically last longer than fast glutamate EPSPs (~5 ms) (contrary to the drawing below and in the textbook)
• PSCs are faster than PSPs due to the membrane capacitance (which usually has a time constant of 1-30 ms).
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Metabotropic Receptors (G-protein-coupled receptors)• Modifies “effectors” though G-proteins
– G-proteins metabolize GTP to GDP. Since they use energy, these receptors are called “metabotropic”
• Often modulatory rather than simply excitatory or inhibitory
• One receptor may alter multiple types of ion channels and other effectors
• Slow kinetics (> 100 ms)
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G-proteins• G-proteins couple G-protein-coupled receptors
to their effectors
• In its inactive state, the alpha subunit of a G-protein binds to GDP
• When a G-protein-coupled receptor binds to neurotransmitter, it induces the G-protein to release GDP and bind GTP
• The G-protein splits into two parts, alpha and beta-gamma. Each of these diffuses in the membrane and is able to activate effector proteins
• The alpha subunit is at GTPase. It hydrolyzes GTP to GDP. This typically occurs after about 1 second.
• The GDP-bound alpha subunit is inactive, and binds to beta-gamma.
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Three types of G-proteins and signalling cascades• Gs:
– alpha subunit activates adenylyl cyclase, which synthesizes cAMP. cAMP activates PKA
• Gi: – alpha subunit inhibits adenylyl cyclase– Beta-gamma subunits activate potassium channels and inhibit calcium channels
• Gq:– Alpha subunit activates phospholipase C, which produces IP3 and diacylglycerol (DAG). IP3
opens ion channel on the endoplasmic reticulum, whish release calcium. DAG activates PKC.
• Each G-protein coupled receptor activates just one type of G-protein
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Direct activation of K+ channels by G-proteins • Gi Beta-gamma subunits activate potassium channels• This is the basis for the GABAB IPSP• They also inhibit Ca2+ channels
GABAB IPSP
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The Gq / Phosphoinositide pathway
• Gq Alpha subunit activates phospholipase C, which produces IP3 and diacylglycerol (DAG). IP3 opens ion channel on the endoplasmic, whish releases calcium. DAG activates PKC. Calcium activates a kinase, potassium channels, and other effectors.
• The next slide shows a slow IPSP mediated by glutamate activation of mGluR1, a receptor that activates this pathway. The calcium activates a K+ channel.`
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Slow Postsynaptic Potentials Mediated by Metabotropic Receptors
• Metabotropic PSPs typically require multiple stimuli at high frequencies– 10 stimuli at 66 Hz (15 ms
intervals) in these examples
• PSPs start after about 100-300 ms and last for a second or longer
• There are many other effects of metabotropic receptors besides PSPs– Modification of ion channels
– Modification of gene expression
GABAB IPSP
Inhibition by glutamate (mediated by mGluR1 and Ca2+ activated K+ channels)
Inhibition and excitation by the same glutamate receptor (mGluR1)
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Second Messengers• The “first” messenger is the neurotransmitter, which mediates
intercellular communication between cells• A second messenger is a small molecule that carries information within
a cell (through diffusion). It mediates intracellular communication.• Examples:
– cAMP– cGMP– IP3
– DAG– Calcium
• Calcium– The most common second messenger– Three main sources
• Voltage-gated calcium channels• NMDA receptors (gated by glutamate)• Intracellular calcium stores in the endoplasmic reticulum
– Calcium is released when IP3 or calcium opens channels in the ER
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Protein Kinases and Phosphatases• The function of proteins (including ion channels) is
modulated through phosphorylation– A phosphate group is attached to a serine, threonine or tyrosine
residue
• Kinases add phosphate groups; phosphatases remove them
• Best known kinases:– Protein kinase A (PKA)– Protein kinase C (PKC)– Calcium-calmodulin-dependent protein kinase (cam-kinase)
• Each kinase or phosphatase modifies a variety of different proteins (effectors)– The set of effector proteins depends on the kinase /
phosphatase