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

Know basic terminology:   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 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 > > 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

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 Outside cell

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 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   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

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