chapter 3 db
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Chapter 3
Chemical Signaling by Neurotransmitters & Hormones
Otto Loewi: Vagusstoff(Vagus Material) Acetylcholine(Ach).
Synapse: coined by Sir Charles Sherrington.
Transmission only from presynaptic to postsynaptic cell.
Pre and post synaptic cells do not touch each other.
Axodendritic Synapses: most common synapses in brain.
o An axon terminal from presynaptic neuron communicates with the dendrite
of the postsynaptic cell.
o Some dendrites have short spines.
o Spines: imp locations for synapses to form.
Synaptic Cleft:The small gap b/n pre and postsynaptic cells that must be traversedby NT molecules after their release. ( about 20nm, 20 x 10^-9m)
Synpatic vesicles: small sac like objects in the axon terminal, filled with thousandsof molecules of NT.
Vesicles : the source of NT release.
Mitochondria: cellular organelles for energy in the cells. ATP production. Needed inlarge amounts in the terminals for various functions such as ion pumping andtransmitter release.
Axosomatic Synapses: b/n a nerve terminal & a nerve cell body. Func similar toaxodendritic synapses.
Axoaxonic Synapses: b/n one axon synapsing on the terminal of another axon.
o Allows the presynaptic cell to alter neurotransmitter release from the
postsynaptic cell directly at the terminals.
o May reduce or enhance NT release from terminal.
o Reduction: presynaptic inhibition ; Enhanced NT release: presynaptic
facilitation.
Neuromuscular Junction:The connection point b/n a neuron and a muscle calledneuromuscular junction instead of a synapse.
o NMJ : many structural and functional similarities to a conventional synapse.
Neurotransmitters: Chemical substances released by neurons to communicatewith other cells.
Imp criteria for NTs
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o The presynaptic cell should contain the proposed substance along with a
mechanism for manufacturing it.
o A mechanism for inactivating the substance should also be present.
o The substance should be released from the axon terminal upon stimulation of
the neuron.
o There should be receptors for the proposed substance on the postsynaptic
cell.
o Direct application of the proposed substance or an agonist drug that acts on
its receptors should have the same effect on the postsynaptic cell asstimulating the presynaptic neuron which presumably would release thesubstance from the axon terminals.
o Applying an antagonist drug that blocks the receptors should inhibit both the
action of the applied substance and the effect of stimulating the presynapticneuron.
Types of NTs
Amino Acids:
o Individual building blocks contained w/in proteins.
o Metabolic Roles like NTs.
o Glutamate & GABA (Amino acid NTs)
Monoamines:
o Possess a single amine group.
o Derived from amino acids by a series of biochemical rxns that include removalof the acidic (-COOH) group of the molecule.
o Amino acid precursor required to precede the rxn.
o Dopamine(DA), Norepinephrine(NE), Serotonin(5-HT)
Acetylcholine(Ach):
o Neither an amino acid nor a monoamine.
o Ach, AAs and MAs form classical NTs.
Neuropeptides:
o Largest group of non-classical NTs.
o Name means peptides found in Nervous System.
o Peptides: small proteins, 3-40 amino acids
o Endorphins & Enkephalins: stimulate the same opioid receptors that are
activated by heroin and other abused opiate drugs.
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o CRF(Corticotropin Releasing Factor) : plays a role in Anxiety.
o Precursor for peptides are protein molecules in which peptides are embedded.
o Protein precursor for each type of peptide is made in the cell body.
o Cell body is the site of all protein synthesis in the neuron.
o The protein is then packaged into large vesicles along with enzymes that will
break down the precursor and liberate the NPT.
o These vesicles are transported to the axon terminals so that release occurs
from the terminals as with the classical transmitters.
o New NPT molecules can only be generated in the cell body and not in the
terminals.
o Replenishment of NPTs slower than classical NTs.
Lipids:
o Fatty substances.
o Anandamide: a lipid in the brain that acts like THC(marijuana)
Gaseous Transmitters:
o Nitric Acid: the best known unusual and intriguing group of NTs.
2 different types of vesicles: small vesicles for classical NTs and large vesicles forNeuropeptides along with classical NTs.
Axon terminals are an imp site for NT synthesis as the enzymes required forproducing a NT are shipped out in large amounts to the axon terminals.
Neuromodulators:
o Dont act exactly like NTs.
o Alter the action of a std NT by enhancing, reducing, or prolonging the
transmitters effectiveness.
o Peptides co-released w/ Classical NTs exhibit modulatory effect.
o NMs characterized as diffusing beyond the synapse to influence cells farther
away.
Neurotransmitter Release, Exocytosis, and Endocytosis
o when a neuron fires an AP, the depolarizing current sweeps down the length
of the axon and enters all of the axon terminals.
o This wave of depolarization has a very imp effect w/in the terminals: Opens
large #s of voltage-sensitive calcium channels, causing a rapid influx of Caions into the terminals.
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o The resulting +se in Ca conc. w/in the terminals is the direct trigger for NT
release.
Fig 3.5
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Exocytosis:
o A fusion of the vesicle membrane w/ the membrane of the axon terminal,
which exposes the inside of the vesicle to the outside of the cell.
o The NT molecules get to the synaptic cleft past the membrane of the axonterminal.
o The vesicle is opened and its NT molecules are allowed to diffuse into the
synaptic cleft.
o NT release occurs at the specialized regions near the Postsynaptic cell called
active zones.
o Docking: Vesicle docks to the active zone.
o Docking carried out by cluster of proteins, some located in the vesicle
membrane and others residing in the membrane of the axon terminal.
o Docking followed by Priming.
o Priming: Readies the vesicle for exocytosis once it receives the Ca(2+)
signal.
o CA(2+) channels : open due to membrane depolarization. Conc in the active
zones near the sites of vesicle docking, so the protein machinery is exposedto particularly high conc of Ca(2+) when the channels open.
o Proteins sensitive to Ca(2+) then cause the vesicle and terminal membranes
to fuse, which allows the vesicle to open and the transmitter to be released.
Fig 3.6
Endocytosis:
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o Endocytosis retrieves the vesicle membrane from the terminal membrane after
exocytosis.
o New vesicles rapidly formed and refilled w/ NTs and get ready for NT release again.
o The continuous release and re-formation of vesicles termed as vesicle recycling.
o Vesicle recycling only w/ small vesicles containing classical NTs but not w/ large
vesicles containing NPTs
o NPTs made in cell body, so recycling of such vesicles cant occur at the axon
terminal.
Neurotransmitter Release
o NT release monitored by the rate of cell firing.
o More rapid the AP firing, more NT being released.
o The probability of the transmitter release from the terminal also important.
o An AP can enter a terminal and open Ca2+ channels but not release any NT.
o The presence of autoreceptors on axon terminals or cell bodies and dendrites are
also imp for NT release.
o An autoreceptor on a particular neuron is a receptor for the same NT released by that
neuron.
o Neurons may possess 2 difft types of AR's: Terminal AutoReceptors;
Somatodendritic AR's
o Terminal Autoreceptors are located at Axon terminals.
o Main function: Inhibit further transmitter release.
o Autoreceptors = Thermostat.
o Imp when the cell is firing rapidly and there are high levels of NT in the Synaptic
Cleft.
o Somatodendritic Autoreceptors are located in the cell body or on dendrites.
o Function: Slow the rate of firing which causes less NT release, as fewer Aps reach
the axon terminals to stimulate exocytosis.
o Ex: A low dose of the drug apomorphine to rats or mice selectively activates the
terminal autoreceptors for DA. This results in less DA release, an overall reduction indopaminergic transmission, and reduced locomotor activity in animals.
o 8-OH-DPAT activates somatodendritic autoreceptors for 5-HT and inhibits the firing of
serotonergic neurons.
o The behavioral effects of 8-OH-DPAT are increased appetite and altered responses on
several tasks used to assess anxiety.
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o Heteroreceptors : the receptors on axon terminals for other transmitters released
at axoaxonal synapses.
o Heteroreceptors differ from AR's b/c they may either enhance or reduce the amount
of transmitter being released from the axon terminal.
Neurotransmitter Reuptake and Enzymatic breakdown
o Enzymatic breakdown within or near the synaptic cleft is imp for NT inactivation.
o This mechanism is very imp for Ach, lipid and gaseous NT's, and also for
Neuropeptide transmitters.
o Alternative mechanism: NT to be removed from the synaptic cleft by a transport
process involving specialized proteins called transporters.
o Transporters are located on the cell membrane.
o This mechanism important for AA transmitters like Glutamate, GABA, and amine
transmitters like DA, NE, 5-HT
o Reuptake: When transport of NT carried out by the same cell that released the
transmitter.
o In most cases NT taken up by postsynaptic cell or nearby glial cell.
o When transporters are blocked, NT molecules remain in the synaptic cleft for a longer
period of time and Neurotransmission is enhanced at those synapses.
o When NTTs are active, some NT molecues removed from the synaptic cleft are
reused by being packaged into recycled vesicles.
o Uptake and metabolic break down are not mutually exclusive processes.
o Terminal AR's modulate NT release but they do not transport the NT.
o Transporters take up the NT from the synaptic cleft, but they are not autoreceptors.
Neurotransmitter Receptors and Second Messenger Systems
o All NT receptors are proteins located on plasma membrane of the cell in most cases.
o Cell possessing a receptor may be a neuron, a muscle cell, or a secretory cell.
o NT binds to a specific site on a receptor molecule, which activates the receptor and
produces a biochemical alteration in the receiving cell that may affect its excitability.
o
Agonist: When a drug mimics the NT and activates the receptor.
o Antagonist: When a drug mimics the NT and inhibits or blocks the receptor
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