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
6.5
1 Synapses
Know basic terminology: Soma Axon Dendrite Synaptic vesicles Synaptic cleft Postsynaptic Presynaptic Glia 6.2
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
2 Multiple types of synapses
Vesicle varieties +
-
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
3 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
Reuptake transporters
Enzymatic degradation metabolism excretion cycling 8.13
4 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 calcium- calmodulin 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 Neuropeptides Enkephalins, substance P, neurotensin, etc. Nonpeptide hormones
5 Receptors
6.5
Receptors
Classification GABA
By Location Postsynaptic ACH
DA
Receptors
Classification GABA
By Location Postsynaptic ACH Autoreceptors
DA
6 Autoreceptors
Presynaptic GABA Somatodendritic Terminal
Release-modulating ACH Synthesis-modulating Impulse-modulating
DA
Receptors
Classification: By Transduction Mechanism Drug, transmitter or hormone Outside cell Receptor
Inside cell Transduction Membrane Effector
Receptor Superfamilies
1. Ligand-gated channels binding site coupled to ion channel transmitter (or drug) gates the channel ionotropic receptors
7 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 Rapid Rapidly reversible
5.9
Ligand-gated channels
Examples: Nicotinic acetylcholine receptor coupled to sodium channel drugs: nicotine, curare
GABAA receptor coupled to chloride channel drugs: sedative- hypnotics
8 G protein-coupled receptors
G protein-coupled receptors
Large family all with 7 membrane- spanning regions
Receptor coupled to G protein, and G protein stimulates effector
Slower than 6.22 ion-coupled
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”
9 G protein-coupled receptors
Examples:
Cholinergic muscarinic
GABA B 5-HT Opioid Dopamine Norepin- ephrine
Second messengers
Are many: Calcium cGMP Phosphoinositides (IP3, diacylglycerol) cAMP
cAMP (cyclic adenosine 3,5- monophosphate)
1 cAMP
2 3
4
5
6 7
8 9 6.22
10 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
11 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
R= regulatory subunit C= catalytic subunit
Transcription factor: CREB (cAMP response element binding protein)
CREB stimulates gene transcription (eg., IEGs)
6.34
12 Convergence on CREB
2nd messengers kinases Multiple signalling pathways can alter gene transcription via same transcription factor 6.35
Summary
Drugs of abuse are very effective in inducing IRGs
6.37 6.37
c-fos mRNA Expression Saline Amphetamine
Home
Novel
13 Sites of drug action
6.2
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
14