The Synaptic End Bulb

1. The Synaptic End Bulb • When the AP arrives at the end bulb, it opens voltage gated Ca2+ channels • Influx of Ca2+ causes exocytosis ofneurotransmittersfromvesicles • Neurotransmitters (NT) bind to postsynaptic receptors • Binding opens ion channels • Influx of ions creates graded potentials • Neurotransmitters are cleared from the synapse • Enzymatic degradation • Reuptake

2. Synaptic Junction • Vesicles merging with the presynaptic membrane to release NT

3. Membrane Channels: Ion Channels • Remember thation channels can have selectivity mechanisms, which allow them to let some ions pass through while excluding other ions • An ion channel that allows anions to cross, but excludes cations

4. Neurotransmitter Effects & Graded Potentials • The effect of a neurotransmitter can be either excitatory or inhibitory • An Excitatory (depolarizing)PostSynaptic Potential is called an EPSP • It results from the opening of ligand-gated Na+ channels • The postsynaptic cell becomes morepositive or depolarized • The postsynaptic cell is more likely to reach threshold • An Inhibitory (hyperpolarizing)PostSynaptic Potential is called an IPSP • It results from the opening of ligand-gatedCl- or K+ channels • The postsynaptic cell becomes morenegative or hyperpolarized • The postsynaptic cell is less likely to reach threshold • Both excitatory and inhibitory neurotransmitters are present in the CNS and PNS • The same neurotransmitter may be excitatory at some synapses and inhibitory in others. • Synaptic effects depend more on the receptor than on the neurotransmitter

5. Ionotropic & Metabotropic Receptors • At some receptors, neurotransmitters do not directly open ion channels • When a neurotransmitter binds to this type of channel, it activates a 2nd messenger system • These are also called metabotropic channels and G protein coupled receptors (GPCR) • These receptors often bring about slower but longer lasting changes, • Some receptors directly open ion channels when neurotransmitters bind • These receptors generally bring about fast acting changes • This type of receptor is called ionotropic

6. GPCR (G Protein Coupled Receptor) • In some cases a GPCR may indirectly open an ion channel • In other cases it may cause long term changes in gene transcription and receptor regulation

7. The Acetylcholine (ACh) Receptor • The ACh receptor at the NMJ is ionotropic • Binding of ACh causes the channel to undergo a conformational change which causes the ion channel to open

8. Agonists and Antagonists • Neurotransmitter effects can be modified and mimicked • Synthesis can be stimulated or inhibited • Release can be blocked or enhanced • Removal can be stimulated or blocked • Receptor site can be blocked or activated • An agonist is anything that enhances the action of a neurotransmitter • An antagonist is anything that blocks the action of a neurotransmitter • Many drugs and toxins function as agonists or antagonists of neurotransmitters

9. Agonist/Antagonist Identification • Strychnine, a component of rat poisons, which blocks postsynaptic glycine receptors • Huwentoxin, a toxin in the venom of Selenocosmia huwenathe Chinese bird spider, which opens Ca2+ channels in the axon terminal, thus increasing the release of neurotransmitter • Diisopropylphosphorofluoridate (DFP), an insecticide which inhibits acetylcholinesterase (AChE), the enzyme that breaks down acetylcholine in the synapse • Muscimol, found in Amanita muscaria mushrooms, which binds to postsynaptic GABA receptor sites • Reserpine (a component of Diupres, an antihypertensive drug), which inhibits the storage of catecholamines in presynaptic vesicles • Cocaine, which stimulates the release of norepinephrine and dopamine from presynaptic terminals • Sertraline (Zoloft), fluoxetine (Prozac), and paroxetine (Paxil), antidepressant drugs, which block the reuptake of serotonin • Chiriquitoxin, a substance secreted by the skin of Atelopus chiriquensis, one of the poison dart frogs of Costa Rica, which blocks voltage gated Na+ channels on the axon • Dihydroxyphenylserine (DOPS), an experimental drug which is converted to norepinephrine in the axon terminals

10. Neurotransmitters • Acetylcholine (ACh) • Neurotransmitter at the NMJ • Synthesized from choline and acetic acid • Inactivated by AChE • Many neuromuscular disorders involve ACh • Many nerve gases and insecticides are AChEinhibitors • Amino Acid Neurotransmitters • Small molecules composed of an amine group (NH2) and a carboxyl group (COOH) • Glutamate • Principal excitatory neurotransmitter in the human brain • Involved in “Chinese Restaurant Syndrome” • Aspartate • Another excitatory neurotransmitter • Aspartame (Nutrasweet) is a combination of aspartate and phenylalanine • Both glutamate and aspartate can be synthesized from glucose • Both glutamate and aspartate are inactivated by glial cell uptake ACh glutamate aspartate

11. Neurotransmitters • Amino Acid Neurotransmitters • g-amino-butyric acid (GABA) • Principal inhibitory neurotransmitter in the human brain • Synthesized from glutamate • Many tranquilizers are GABAagonists • These include Valium and Xanax • Picrotoxin, a GABAantagonist, is a convulsant • Reuptake is a significant factor in GABA inactivation • Glycine • Another inhibitory neurotransmitter • Strychnine, an age old poison, is a glycineantagonist • As you might expect, it causes convulsions • Strychnine was often sold as rat poison • Derived from the plantStrychnos nux-vomica • Reuptake is a significant factor in glycine inactivation GABA glycine

12. indole Neurotransmitters • Monoamine Neurotransmitters • Small molecules other than amino acids which contain an amine group (NH2) • Catecholamines have a catechol group • Indoleamines have an indole group • All monoamine neurotransmitters are inactivated by monoamine oxidase (MAO) • Catecholamine neurotransmitters are also inactivated by catechol-O-methyl transferase (COMT) • Norepinephrine (noradrenalin) (NE) • An important neurotransmitter in the brain, and also in the ANS • Raises blood pressure in the ANS • Reuptake is a significant factor in NE inactivation • Cocaine stimulates the release of NE & blocks reuptake • Methamphetamine also stimulates NE release & blocks reuptake • Propanalol, anNE antagonist, is an antihypertensive • Pseudoephedrine (Sudafed)is anNE agonist • Phenylpropanolamine (PPA)is anNE agonist catechol NE

13. NE Neurotransmitters • Dopamine (DA) • Synthesized from phenylalanine from the diet • Precursor to norepinephrine (NE) • Cocaine stimulates the release of DA and blocks its reuptake • Methamphetamine also stimulates the release of DA and blocks its reuptake • Parkinson’s Disease is a degenerative disease resulting from the death of DA neurons in the basal ganglia • Haloperidol (Haldol) and clozapine (Clozaril) are DA antagonists used in treating schizophrenia • Serotonin (5-HT) • An indoleamine neurotransmitter • Synthesized from tryptophan • Only about 2% of the body’s serotonin is found in the brain • Reuptake is a significant factor in 5-HT inactivation • Many popular antidepressants are SSRI’s (Prozac, Zoloft, etc.) • LSD and mescaline are 5-HTagonists • Some 5-HTantagonists are used to suppress vomiting in chemotherapy patients 5-HT

14. Neurotransmitters Bufo alvarius (Sonoran Toad)

15. Neurotransmitters • Compounds secreted by the parotid glands • Bufogins • Bufotalins • Bufotenin • Bufotenin • Dimethyltryptamine (DMT) • Hallucinogen • Agonist of 5-HT • “Them Toad Suckers” Bufo alvarius (Sonoron Toad)

16. adenosine Neurotransmitters • Purine/Nucleoside Neurotransmitters • In addition to being the body’s energy currency, ATP & ADP are neurotransmitters • Adenosine, the base molecule, is an inhibitory neurotransmitter • Caffeine is an adenosineantagonist • Peptide Neurotransmitters • Composed of up to 30 amino acids • Substance P produces pain when released • Capsaicin, the active compound in hot peppers, stimulates Substance P release • Endorphins and enkephalins inhibit the release of Substance P • Morphine and heroin are natural antagonists of Substance P • Vicodin (hydrocodone) and Percocet (oxycodone) and other opioids are synthetic antagonists of Substance P

17. Neurotransmitters Substance P

21. Carbachol is an agonist of ACh • Tubocurarine is an antagonist of ACH • Which portion of the ACh molecule binds to the receptor?