1. Neurotransmitters, Neurotransmitter receptors and their effects
We’re talking signals and what they mean to a neuron! What happens if we block signals?
No specific chapter reading for this.....stick to the slides!

2. General Sequence of Events at Chemical Synapses
NTS synthesis and storage in presynaptic cell
NTS release by exocytosis (Ca++ triggered event)‏
Diffusion across cleft
NTS reversibly binds to receptors (LGC) and opens gates, allowing ion diffusion
NTS removal from synapse (destruction, diffusion away)‏
NTS reuptake by presynaptic cell for recycling
VOCC
Ca+2

3. NTS Action
NT diffuses across synaptic cleft to bind to receptor (LGC) on postsynaptic membrane
Can generate an electric signal there (EPSP’s or IPSP’s)‏
These are graded potentials (more channels, more charge flux)‏
Effect depends which ions are allowed to diffuse across membrane, how many and for how long. Effect depends on the selectivity of the channel.
What if….. the LGC are…..
Na+ selective
K+ selective
Cl- selective
What happens to the voltage on the postsynaptic cell? Is it an EPSP or an IPSP?

4. Neurotransmitters (NTs)‏
The substance must be present within the presynaptic neuron
Must be released in response to presynaptic depolarization, which must occur in a calcium dependent manner
Specific receptors must be present on the postsynaptic cell
NT must be removed to allow another cycle of NT release, binding and signal transmission
Removal: reuptake by presynaptic nerve or glia or degradation by specific enzymes or a combination of these

5. Small molecule neurotransmitters
Acetylcholine (ACh)‏
ACh (“cholinergic”)‏
Amino Acid Neurotransmitters
Glutamate
Aspartate
GABA
Glycine
Catecholamines
Norepinephrine
Epinephrine
(“adrenergics”)‏
Dopamine
Indoleamine
Serotonin
Imidazolamine
Histamine
Peptide Neurotransmitters (usually 3-30 aa’s long)‏
Met-enkephalin, vasopressin (ADH), many others

6. Acetylcholine Used in NMJs
Sympathetic and parasympathetic ganglia in PNS
Acetylcholine esterase (AChE)‏
“cholinergic” neurons have ChAT enzyme (choline acetyl transferase

7. Glutamate Very important in CNS Nearly all excitatory neurons use it
Antagonists to Glutamate receptor help stop neuronal death after stroke
Too much- excitotoxicity due to unregulated calcium influx
Too little, leads to psychosis (delusional, paranoid, lack of contact with reality

8. GABA and Glycine Major inhibitory neurotransmitter in CNS
Decreased GABA- seizures
Anticonvulsants target GABA receptors or act as GABA agonists
Valium- increases transmission of GABA at synapses
Benzodiazepines and ethanol trigger GABA receptors……use benzodiazepines during ethanol detox.
Glycine- also inhibitory
Mostly in spinal cord and brainstem motor neurons

9. Catecholamines Derived from amino acid tyrosine - common precursor
Phenylalanine hydroxylase
phenylalanine
Catecholamines
Derived from amino acid tyrosine - common precursor
Removed by reuptake into terminals or surrounding glial cells via sodium dependent transporter
Mono-amine oxidase (MAO) and catechol o- methyltransferase (COMT) degrade catecholamines
Anti-anxiety agents- MAO- inhibitors
DO NOT MIX SYMPATHOMIMETICS WITH MAOI’s!

10. DISORDER OF PHENYLALANINE METABOLISM Phenylketonuria (PKU)‏
A genetic, autosomal recessive disorder (1:20,000 births)‏
Lack of enzyme phenylalanine hydroxylase
Inability to convert phenylalanine (aa) from the diet to tyrosine (aa)‏
Accumulation of breakdown products of excess phenylalanine leads to neuronal degeneration, seizures, poor motor development and irreversible mental retardation in a developing child.
Testing at birth in many states, also CA. Heel stick blood sample
Prevented by dietary restriction on phenylalanine. No whole protein; source of all aa’s minus this one. At least through to adulthood, while nervous system is developing.
Maternal PKU: what is it?

11. Dopamine Parkinson’s Disease (Parkinsonism)‏
Loss of dopamine from neurons in substantia nigra of midbrain
Resting tremor, “pill rolling”, bradykinesia, gait
Treat with L-dopa. (Crosses BBB) or MAO inhibitors
Side effects (hallucinations, motor)‏
The Case of the Frozen Addicts, by Langston, J. W

12. Serotonin Synthesized from tryptophan
Also known as 5- hydroxytryptamine
(5-HT)‏
SSRI’- selective serotonin reuptake inhibitors are anti-depressant drugs
Ecstasy causes more release!
Mood elevator, “feel- good” neurotransmitter

14. Ionotropic Receptors
Nicotinic AChR
Serotonin Glutamate
GABAA
Glycine

15. Metabotropic Receptors
Muscarinic Acetylcholine receptor
Amanita muscaria
Parasympathetic effectors stimulated
Increased saliva, tears, diarrhea
Antidote is atropine.
alpha and Beta-Adrenergic receptor
alpha1-receptors:
bind G protein, activate inositol triphosphate and diacylglycerol as second messengers
alpha2 -receptors:
bind the inhibitory G-protein, restrain the adenyl cylase system, reduce cAMP levels
beta-receptors:
bind adenylate cyclase-stimulating G-protein, use cAMP as second messenger.
Some glutamate receptors, many, many others

16. Major Intracellular Transduction Pathways Used by metabotropic receptors
Signaling molecule
Cell surface
receptor
G protein
Effector protein
Second messenger
cAMP
IP3/D AG
Late effectors
Target protein
cAMP Pathway
IP3 Pathway

17. Signaling by GPCRs

18. Adenylate cyclase and guanylate cyclase
Make cyclic AMP and cyclic GMP

19. Protein kinase A dissociates when activated by cAMP
Regulatory subunit
Catalytic subunit
- Add/remove phosphates to/from enzymes to activate or deactivate them

20. Phosphatases remove phosphorylation; kinases add
Better to think in terms of changes in activity rather than activation (i.e. always basal state of activation)‏

21. NE
adrenergic
receptor mechanism   C 
GTP R R C
PKA R C 
cAMP

22. Inositol Trisphosphate & DAG

23. Aspects of IP3 signaling
Production of IP3
Release of Intracellular Calcium
PKC
Aspects of IP3 signaling

24. NT postsynaptic response and gene expression
Open channels
Alter gene expression
Second messenger activation can lead to phosphorylation of proteins that in turn regulate gene transcription

25. Spastic paralysis vs. flaccid paralysis
Drugs and Toxins
Spastic paralysis vs. flaccid paralysis

26. Sodium VGC Blockers Lidocaine- used as anesthesia
Tetrodotoxin-puffer fish and newts (TTX)‏
Saxitoxin- caused by red tide; dinoflagellate; accumulates in shellfish (SXT)‏
Flaccid paralysis

27. Vesicle blockers Clostridium botulinum:
It is a protease that breaks down one of the fusion proteins (docking proteins that anchor the vesicle to the membrane)
Inhibits neurotransmitter release
Undercooked turkey; dented cans
Flaccid paralysis
“BOTOX”

28. mACH-R blocker/ competitor
Atropine
Flaccid paralysis
Smooth muscle, heart, and glands

29. nACH-R blocker/ competitor
Curare
From tree sap
Causes flaccid paralysis
Large dose: asphyxiation

30. AchE Blockers Neostigmine Physostigmine Spastic paralysis
Myasthenia Gravis- ptosis

31. AchE irreversible inhibitor
DFP- di-isopropyl fluorophosphates
Sarin
Spastic paralysis
Ventilator until AchE turnover

32. Inhibitory Neuron Blockers
Tetanus exotoxin
Blocks release of inhibitory neurotransmitters
Muscles can’t relax
Spastic paralysis
Opposing flexor and extensor muscles contract

33. Spider Venom Black widow: causes Ach release
Lack of inhibitory neurotransmitters
Spastic paralysis
Brazilian Wandering Spider and Viagra?
Spider venom increases NO release
Viagra blocks enzyme that degrades NO
Most venomous of all spiders/ more human deaths