Transcript 181lec5

Psych 181: Dr. Anagnostaras
Lecture 5
Synaptic Transmission
Introduction to synaptic transmission
Synapses
(Gk., to clasp or join)
Site of action of most
psychoactive drugs
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6.5
Synapses
Know basic terminology:
 Soma
 Axon
 Dendrite
 Synaptic vesicles
 Synaptic cleft
 Postsynaptic
 Presynaptic
 Glia
7
8
5
6
1
6.2
2 3 4
Synapses
Dendrites &
spines
3.10
Synapses
Types of cell-cell junctions
Tight junctions
 membranes fused
Gap junctions
 close juxtaposition (2-4 nm)
 electrical synapse
Chemical synapses
 synaptic cleft (20-30 nm)
 polarized
Multiple types of synapses
Spherical agranular Spherical granular
vesicles
Vesicle varieties
+
Reciprocal junction
Flattened vesicles
-
6.3
6.4
Multiple types of synapses
Multiple patterns of connectivity
 Axodendritic
 Dendrodendritic
 Axoaxonic
 Axosomatic
 etc.
6.1
Steps in synaptic transmission
Synthesis
 Transport
 Storage
 Release
 Inactivation

Release
Excitation-secretion coupling








Depolarization
Open voltage-gated Ca++ channels
Ca++ influx
Bind to Ca++ -calmodulin protein kinase
Phosphorylation of synapsin I
Movement of vesicles to release site
Exocytosis
Diffusion
Exocytosis
6.17
Inactivation
HVA
Reuptake

transporters
Extracellular
DOPAC
DOPAC
Monoamine
oxidase
Enzymatic
degradation
metabolism
 excretion
 cycling
Tyrosine
Cytoplasmic
DA

DOPA
Releasable
DA
Dopamine
transporter
8.13
Extracellular DA
COMT
3-MT
Sample question
In which of the following are the events listed in the correct temporal order
(i.e., the temporal order associated with excitation-secretion coupling)?
(a) Depolarization > calcium influx > phosphorylation of synapsin >
activation of calcium-calmodulin protein kinase > exocytosis
(b) Depolarization > calcium influx > activation of calcium-calmodulin
protein kinase > phosphorylation of synapsin > reuptake > exocytosis
(c) Exocytosis > phosphorylation of synapsin > calcium influx > activation
of calcium-calmodulin protein kinase > depolarization > calcium influx
(d) Enzymatic degradation > exocytosis > activation of calciumcalmodulin protein kinase > phosphorylation of synapsin > calcium influx
> depolarization
(e) Depolarization > calcium influx > activation of calcium-calmodulin
protein kinase > phosphorylation of synapsin > exocytosis > enzymatic
degradation
Neurotransmitters
Two major types:
“Classical”
small water soluble molecules with amine
 formed from dietary precursors

Neuropeptides

protein synthesis
Neurotransmitters
Phenylethylamines

DA, NE, E, tyramine, etc.
Indoleamines

5-HT, tryptamine, melatonin, etc.
Cholinergics
Amino acids GABA, glutamate, etc.
Neuropeptides

Enkephalins, substance P, neurotensin, etc.
Nonpeptide hormones
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Receptors
6.5
Receptors
Classification
GABA
By Location

Postsynaptic
ACH
DA
Receptors
Classification
GABA
By Location
Postsynaptic
 Autoreceptors

ACH
DA
Autoreceptors






Presynaptic
Somatodendritic
Terminal
GABA
Release-modulating
Synthesis-modulating
Impulse-modulating
ACH
DA
Receptors
Classification:
By Transduction
Mechanism
Drug, transmitter
or hormone
Outside cell
Receptor
Transduction
Inside cell
Membrane
Effector
Receptor Superfamilies
1. Ligand-gated channels
binding site coupled to ion channel
 transmitter (or drug) gates the channel
 ionotropic receptors

Receptor Superfamilies
1. Ligand-gated channels
2. G protein-coupled
receptor coupled to G protein
 G protein activates effector
 metabotropic receptors

Ligand-gated channels




Ligand opens channel
Ions flow down conc.
gradient
Extracellular side
Rapid
Closed
Rapidly
Binding
reversible
Cytoplasmic side
Open
5.9
Ligand-gated channels
Examples:
Nicotinic acetylcholine receptor
coupled to sodium channel
 drugs: nicotine, curare

GABAA receptor
coupled to chloride
channel
 drugs: sedativehypnotics

G protein-coupled receptors
G protein-coupled receptors


Large family all
with 7 membranespanning regions
Receptor

Receptor coupled


to G protein, and G Ion
channel
G protein
protein stimulates
effector
Second
messenger

Slower than
ion-coupled
6.22
Effector
enzyme
Precursor
G protein-coupled receptors
Two classes:
G protein directly coupled to ion channel
 effector is ion channel
G protein coupled to 2nd messenger system
 effector is enzyme that promotes formation
of intracellular “second messenger”
G protein-coupled receptors
Examples:
Cholinergic
muscarinic
 GABA B
 5-HT
 Opioid
 Dopamine
 Norepinephrine

Second messengers
Are many:
Calcium
 cGMP
 Phosphoinositides
(IP3, diacylglycerol)
 cAMP
Receptor


cAMP
(cyclic adenosine 3,5monophosphate)

Ion
channel


G protein
Second
messenger
Effector
enzyme
Precursor
1
Receptor
cAMP
3
2
Gs
4
cAMP
Adenylyl
cyclase
ATP
5
6 Activate protein kinase
7 (phosphorylate protein)
8
(dephosphorylate by
phosphoprotein
phosphatase)
Biological
response
9
6.22
Protein phosphorylation
Changes structure/function of protein
Consequence depends on function of protein
 ion channel proteins
 enzymes
 cytoskeletal proteins
 vesicular proteins
 receptors
 gene regulatory proteins
Second messengers and protein kinases have many targets
from P. Greengard, Science, 2001
from P. Greengard, Science, 2001
Gene regulation
Second messengers can alter gene regulation:



Activate transcription factors
Regulate transcription
 enhance or supress
If enhance - new gene products
Gene regulation
Two phases of gene activation:
Initial phase
 induction of immediate-early genes (IEGs)
(e.g., cfos, c-jun, zif-268, etc.)
 protein products initiate 2nd phase
Second phase
 induction of “late-onset genes”
 products that alter cellular function
Gene regulation by cAMP
Agonist
Receptor
R= regulatory subunit
C= catalytic subunit
Plasma membrane
AC
G
Transcription factor:
CREB (cAMP response
ATP
cAMP
RR
R R Protein
C C kinase A
element binding protein)
Nuclear
membrane
CREB stimulates gene
transcription (eg., IEGs)
mRNA
C C
Nucleus
P
CREB
CRE
6.34
Convergence on CREB
NGF
Plasma
membrane Ca2+
Neurotransmitter
or drug
Receptor
Receptor
2nd messengers
kinases
Multiple signalling
pathways can alter
gene transcription
via same
transcription
factor
Ras
CREB-K
Ca2+
cAMP
CaM-K
PKA
Nuclear
membrane
CREB
Nucleus
Gene transcription
6.35
Summary
First messengers
Neurotransmitters
Receptors
Drugs of
abuse are
very effective
in inducing
IRGs
Coupling factors
G proteins
Second messengers
Ca2+ Diacylglycerol IP3 cAMP cGMP
Protein kinases
Third messengers
CREB-like
Nuclear
membrane transcription factors
Fourth messengers
fos-like
Transcription factors
6.37
Other
genes
6.37
c-fos mRNA Expression
Saline
Home
Novel
Amphetamine
Sites of drug action
7
8
5
6
1
6.2
2 3 4
Sample question
Which of the following classes of drug action would
have in common the effect of increasing synaptic
transmission?
(a) facilitation of release; block reuptake; inhibition of synthesis
(b) blockade of the release modulating autoreceptor; facilitation
of release; receptor agonist
(c) receptor agonist; receptor antagonist; synthesis inhibition
(d) reuptake blocker; facilitation of release; receptor antagonist
(e) blocks metabolism; block reuptake; inhibits synthesis