Download - Neurotransmission and Signal Transduction
Neurotransmission and Signal Transduction
Paul Glue
Objectives
•Review aspects of chemical transmission and intracellular signalling in the brain
•Role of neurotransmitter/signal transduction abnormalities in selected neurological/psychiatric disorders
–Rational pharmacology for nervous system disorders
–Prediction of side-effect profile
Basic Neurotransmission2…releasing neurotransmitter
into synapse...
1: Presynaptic neuron fires...
3…transmitter interactswith a post-synaptic receptor
which may...
4…activate second messenger pathways….
5….open an ion channel….
6…which may lead to cell firing; inhibition of
firing; genome activation,peptide production etc….
7…which may translate into perception; memory; emotion; autonomic homeostasis; endocrine response etc….
8…and in pathological states may translate into depression, seizures, neurodegeneration, etc….
Neurotransmission• Based on anatomy of neuronal pathways• Based on diffusion of chemical signals
– signalling may extend beyond the site of release to adjacent synapses
• Based on speed of response– fast: glutamate (+); GABA (-)– slow/modulatory: serotonin, norepinephrine, neurohormones
• Based on neuronal responses– chemical signal from proximal neuron may produce :
• nerve firing/inhibition of firing• increased activity of second messengers• gene transcription• increased/decreased receptor density/sensitivity• increased/decreased synaptic connections
(synaptic plasticity)
Characteristics of 4 Major Receptor Types
Receptor Timescale Effector Coupling Example
Ligand-gated ion channel
Milliseconds Channel Direct Nicotinic AChR
G-protein-coupled receptor
Seconds Channel/ enzyme
G-protein Muscarinic AChR
Kinase-linked receptor
Minutes Enzyme (tyrosine kinase)
Direct or indirect
Insulin
Nuclear receptor Hours Gene transcription
Via DNA Thyroid, estrogen
Ligand-Gated Ion Channels- Agonist-regulated, ion-
specific, membrane spanning channels
- Passage of ions alters membrane potential/ionic composition
- Made up of subunits
Examples: Nicotinic cholinergic, GABA-A, glycine, glutamate, aspartate, 5-HT3 receptors
G-Protein Coupled Receptors- 7 transmembrane-spanning -
helices- Associated with trimeric GTP-
binding regulatory proteins- Agonist binding to extracellular
domain- GTP activates G-protein, which
then activates specific effector proteins
- Individual cells can express up to 20 GPCRs
Examples: NE, 5-HT, DA, histamine, opioids, (>750)
Video clip
GαGDP
β γEffectorGα
GDP
β γEffector
Intracellular Signal Transduction
GαGDP
β γEffector
Agonist binds to G-Protein-coupled receptor
GαGDP
β γEffector
G-Protein complex is activated by a GDPGTP switch in Gα subunit
GTP
GαGTP
β γEffector
GDP
GαGTP
β γEffector
Activated Gα and β/γ subunitsmove to regulate effectors
G effects on: Gαs: adenylyl cyclase Adenylyl cyclase Gαi: adenylyl cyclase Phospholipase C Gαo: Ca++ currents PI-3-kinase Gαq: phospholipase C Inward-rectifier Gα13: RHO GTP exchange K+ currents catalyst
GαGTP
β γEffector
A G-protein receptor kinase phosphorylates the receptor’s C-terminal tail
GRK
GRK
P
GαGTP
β γEffector
Arrestin binds to the phosphorylatedC-terminal tailReceptor-G protein interaction is prevented and receptor activity is halted c-Src (tyrosine kinase) binds to arrestin
P
Arrestinc-Src
GαGTP
β γEffector
Arrestin binds to clathrin (vesicular protein)c-Src phosphorylates dynamin; endocytosisof receptor commences
P
Arrestinc-Src
DynP
DynP
GαGTP
β γEffector
P
Arrestinc-Src
DynP
DynP
P
Arrestinc-Src
DynDynP P
GαGTP
β γEffector
P
Arrestinc-Src
GαGTP
β γEffector
Endocytosis is complete.Agonist dissociates and Receptor is dephosphorylated
GαGTP
β γEffector
Endocytosis is complete.Agonist dissociates and Receptor is dephosphorylated
GαGTP
β γEffector
Receptor may be reinserted in membrane…
Or may remain in vesicle in cytoplasm in an inactive state….
Or may be degraded by lysosomes
VIDEO
Intracellular Signaling
• Post-receptor signal transduction occurs via networks of signaling proteins (2o and 3o messengers)– transform multiple external stimuli into appropriate cellular
responses. • Molecules in this network form ordered biochemical
pathways– signal propagation occurs through the sequential protein-protein
and small molecule-protein interactions. • Signaling components are organized into macromolecular
assemblies (adapter proteins)– organize signaling pathways into distinct functional entities – critical for efficiency and specificity of signaling– various levels of complexity (simple to complex multi-domain
proteins)
PKA phosphorylates K channels
PKAcAMP
PKAcAMP
PKAcAMP
cAMP activates protein kinase A
AC
cAMPATP
AC
cAMPATP
AC
cAMPATP
G-protein stimulates adenylyl cyclase to convert ATP to cAMP
GTP GDP GTP GDP GTP GDP
Receptor activates G-protein
Signal Amplification CascadeTransmitter
Transmitter activates receptor
Synaptic Plasticity• Historical View:
– Synapses and overall neuronal structure relatively fixed.
– Learning and other mental processes occurred via adjusting the threshold and firing rate between the synapses
• Contemporary View:– Neuronal signaling and responsiveness are highly dynamic and adaptive
– Changes may occur in response to developmental or experiential input
– Changes may occur at multiple levels (molecular, transcriptional, cellular)
Some Of The Major Intracellular Signalling Pathways Involved In Regulating Neural And Behavioral Plasticity
Transduction at multiple levels - Vision
Environmental stimulus Light waves
Specific receptor and second messenger
G-protein associated with rhodopsin in rods/cones
Sensory nerve Depolarization of neurons in optic N
Primary cortex Occipital cortical neurons
Secondary cortices Localized processing of specific categories (shape, movement, color, faces)
Association cortices Organization of images in temporal lobes. Memory and affective input
Higher processing DLPFC (executive functioning, planning, decision making)
Examples of Dopaminergic Plasticity
– Desensitization (agonists):• Rapid loss of euphoric effects of cocaine• Loss of efficacy of PD treatment over time (?or due to
disease progression)
– Sensitization (agonists)• Increased dendrite density in N Acc, PFC after chronic
cocaine/amphetamine– May explain phenomenon of behavioral sensitization
– Sensitization (antagonists)• Tardive dyskinesia possibly caused by striatal D2
hypersensitivity, following chronic neuroleptic treatment
NE/5HT plasticity– Desensitization
• Short term use of antidepressants– Reduction of incidence/severity of earl;y side effects (GI symptoms,
insomnia, anxiety)
• Chronic administration of antidepressants – Postsynaptic receptors – therapeutic
• Abrupt antidepressant withdrawal– Presynaptic autoreceptors – possible cause of withdrawal symptoms
after stopping antidepressants
– Synaptic/neuronal growth• Serotonin depletion reduces synaptic density hippocampal neurogenesis by antidepressants dendritic growth by lithium
Other plasticity examples…
• Tolerance to alcohol and ….
• Alcohol withdrawal and ….
• Acute BDZ tolerance (waking post O/D) vs chronic tolerance
• Tolerance to opioids
• Hypertensive rebound after stopping clonidine
Conclusions• Chemical neurotransmission and subsequent signal transduction are
the main processes for neuronal communication – Adaptive, plastic process
• Role of specific neurotransmitters in selected nervous system disorders– Biochemical basis for neurological and psychiatric disorders – Choice of rational pharmacotherapy for nervous system disorders– Also may predict side-effect profile of existing and new treatments
• Range of potential therapies will expand as our understanding of central transmission/signal transduction becomes more sophisticated