The Synaptic End Bulb

• When the AP arrives at the end bulb, it opens voltage gated Ca2+ channels

• Influx of Ca2+ causes exocytosis of neurotransmitters from vesicles

• 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

Synaptic Junction

• Vesicles merging with the presynaptic membrane to release NT

Membrane Channels: Ion Channels

• Remember that ion 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

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 more positive 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-gated Cl- or K+ channels The postsynaptic cell becomes more negative 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

Ionotropic & Metabotropic Receptors

• Some receptors directly open ion channels when neurotransmitters bind These receptors generally bring

about fast acting changes This type of receptor is called

ionotropic

• 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,

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

The Acetylcholine (ACh) Receptor

• Binding of ACh causes the channel to undergo a conformational change which causes the ion channel to open

• The ACh receptor at the NMJ is ionotropic

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

Agonist/Antagonist Identification• Strychnine, a component of rat poisons, which blocks postsynaptic glycine

receptors

• Huwentoxin, a toxin in the venom of Selenocosmia huwena the 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

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 AChE inhibitors

• 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

Neurotransmitters

• Amino Acid Neurotransmitters -amino-butyric acid (GABA)

Principal inhibitory neurotransmitter in the human brain

Synthesized from glutamate Many tranquilizers are GABA agonists

These include Valium and Xanax

Picrotoxin, a GABA antagonist, is a convulsant Reuptake is a significant factor in GABA

inactivation

Glycine Another inhibitory neurotransmitter Strychnine, an age old poison, is a glycine

antagonist As you might expect, it causes convulsions Strychnine was often sold as rat poison Derived from the plant Strychnos nux-vomica

Reuptake is a significant factor in glycine inactivation

GABA

glycine

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, an NE antagonist, is an antihypertensive Pseudoephedrine (Sudafed) is an NE agonist Phenylpropanolamine (PPA) is an NE agonist

catechol

indole

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-HT agonists Some 5-HT antagonists are used to suppress vomiting in chemotherapy patients

NE

5-HT

Neurotransmitters

Bufo alvarius (Sonoran Toad)

Neurotransmitters

Bufo alvarius (Sonoron Toad)

• Compounds secreted by the parotid glands Bufogins Bufotalins Bufotenin

• Bufotenin Dimethyltryptamin

e (DMT) Hallucinogen Agonist of 5-HT “Them Toad

Suckers”

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 adenosine antagonist

• 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

adenosine

Neurotransmitters

Substance P

• Carbachol is an agonist of ACh

• Tubocurarine is an antagonist of ACH

• Which portion of the ACh molecule binds to the receptor?