Transcript Biology for Engineers: Cellular and Systems Neurophysiology

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
• 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”
Distribution of Major Modulatory Neurotransmitters
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
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
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
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 channels
Metabotropic, 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.
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
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
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).
Glutamate EPSCs
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)
G-proteins
• G-proteins couple G-protein-coupled receptors
to their effectors
• In its inactive state, the alpha subunit of a Gprotein 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.
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
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
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.`
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)
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
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