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