Neurophys 4 Ex1

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• Protein synthesis occurs in the soma of the cell body in an energy

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dependent. Neurotransmitters are highly concentrated in vesicles. ATP
is also present

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Most protein synthesis occurs in the soma and proteins appear to move toward

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the periphery. This is
an active, energy-dependent process. Vesicular and non-vesicular transport occurs and transported
proteins include synthetic enzymes for neurotransmitters, channel and secretory proteins and
cytoskeletal components.

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Transport is bidirectional, but faster (410 mm/day) in the

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orthograde than in the retrograde direction.
There are other motor proteins involved in slow transport. Dendritic transporters also exist.

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 Vesicular Transport (Peptide Transmitter/ dense core vesicles)- Is much faster where vesicles are formed at the

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cell body including possibly more than one prepeptide precursor. At the terminal end, enzymes modify the prepeptides to produce peptide neurotransmitters.

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 Non Vesicular Transport ( small molecule transmitters/ clear vesicles)- is a much slower transport in which the enzymes

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are synthesized in the cell body and are transported down the axon where they synthesize and package neurotransmitters for release

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• Impt to note that NT synthesis is occurring within

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the vesicle (example: NE synthesis from DOPA occurs inside the presynaptic vesicle because dopamine Beta hydroxylase is inside the vesicle and for epinephrine synthesis to occur, the NE must come out of vesicle either through a VMAT1 or VMAT2 receptor

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Depolarization requirement for neurotransmitter release

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Depolarization requirement for neurotransmitter release (Figs 14-22)
1) Coordinated actions of voltage sensitive Na+ and K+ channels allow for impulse propagation.
2) Block of Na+ channels (tetrodotoxin-TTX) prevents depolarization and block of K+ channels
(Tetraethylammonium-TEA) sustains depolarization.
3) Voltage-Gated ion channels have several forms. Their structure dictates mechanisms of
activation, inactivation and the species of ion conducted.
4)”Channelopathies” are specific clusters of mutations in ion channel proteins that dictate human
diseases
5) NT Release is proportional to presynaptic depolarization.
6) Local depolarization will substitute for propagated impulse .
7) Ca2+ entry is proportional to neurotransmitter release.
8) Voltage gated Ca2+ channels exist at axon terminal. These are different from the cardiac
channels

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• Synaptic potentials
 Increasing signal strength from the action potential results in

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increased release of neurotransmitters

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 Transmitter release requires presynaptic activation either through

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local depolarization of the presynaptic membrane or direct injection of calcium current (the more calcium, the more transmitter will be released)
• Calcium channels are voltage sensitive

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o Neurotransmitter release involves

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 Action potential conduction requires coordination of voltage-sensitive Na and K channels
- Voltage Gated Ion forms

- An increased signal strength increases the amount of neurotransmitter released (summation)
 Ca entry is necessary for the release of a neurotransmitter
- An increased signal strength increases the amount of neurotransmitter released (summation)
 Ca entry is necessary for the release of a neurotransmitter
 An increased signal strength increases the amount of neurotransmitter released (summation)
 Ca entry is necessary for the release of a neurotransmitter

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 Action potential conduction requires coordination of voltage-sensitive Na and K channels

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• Sodium channels start depolarization and close fast while K channels close slowly and repolarize
• Tetrodotoxin (TTX) blocks Na channels and prevents depolarization
• Tetrathylammonium (TEA) blocks K channels and sustains depolarization

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 Voltage Gated Ion forms: are all voltage dependent mechanisms though the channels are different according to what ion they are permeable to

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• Activation of the channel may cause a rotation of a transmembrane domain which causes a change in pore confirmation allowing certain ions to move through

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 Ca entry is necessary for the release of a neurotransmitter

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• Direct injection of Ca will evoke neurotransmitter release; the same reaction as depolarization.
• The voltage gated channels on the axon terminals are different from the cardiact channels

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Possible mechanism for Ca2+ -mediated neurotransmitter

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1) Ca2+ - gated channels for Ca2+-induced Ca2+ influx in addition to Voltage-gated
channels.
2) Ca2+ -sensitive proteins are clustered around sites of Ca2+ entry.
3) A large family of calcium-sensitive vesicle associated membrane proteins and Ca2+-
sensitive presynaptic membrane proteins exist (SNAPs, SNAREs etc.) Calcium influx
and subsequent phosphorylations may mediate vescicle fusion through these proteins.
4) Proteins such as synapsin participate in vesicle “staging” by binding to vesicles and to
actin. This is sensitive to phosphorylation.
5) G protein subunits (both small GTPases and heterotrimeric G proteins) may play a
direct role in modulating neurotransmitter release.
6) Vesicle membrane recycles

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• Calcium
o causes vesicles containing neurotransmitters to fuse to the presynaptic membrane and release the contents into the synaptic cleft via SNARE proteins that pull the vesicle towards the membrane, calcium binds to synaptotagmin, which catalyzes

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the fusion of the vesicle with the membrane


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• Synapsin Regulates the number of

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synaptic vessels available for release by exocytosis
o This is a vesicular protein that binds the vesicle to an actin microfilament

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o Neurotransmitter release hypothesis

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 Vesicle hypothesis
 Channel hypothesis

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 Vesicle hypothesis

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• Vesicle fuses with inner membrane and releases NT (mostly) though there is some NT release that is gated

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 Channel hypothesis / Gated hypothesis

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• neurotransmitters aren’t contained in vesicles and are just released through voltage gated channels in the presynaptic membrane; so it’s voltage dependent release and the time of channel opening is proportional to NT released

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o Neurotransmitter receptors characteristics

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 Transmembrane proteins
 Rapid and reversible agonist binding
 Stereoselectivity
 Imperfect selectivity
 One neurotransmitter can influence multiple receptors
 Multiple affinity states for agonist binding

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 Rapid and reversible agonist binding

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• Antagonists are also ligands, but only agonists induce active conformations of the receptor

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 Stereoselectivity

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• Specific binding sites
• All have saturable binding kinetics

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 One neurotransmitter can influence multiple receptors

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• A given NT may exert both rapid and delayed effects on such receptors

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 Multiple affinity states for agonist binding

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• Follows ligand-binding kinetics

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Neurotransmitter receptors are
transmembrane proteins and they're main characteristic

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They display saturable binding kinetics.
2. Multiple affinity states exist

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Agonists and Antagonists are both ligands, but only the former induce

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the active
conformation of the receptor.

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Receptors couple to effector molecules:

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transduction.
1. Multiple receptors exist for a given neurotransmitter.
2. A given neurotransmitter may exert both rapid and delayed effects

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Receptors are ion channels or they are coupled, indirectly, to systems that

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alter ion
conductance and neuronal excitability. This includes synaptogenesis.

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 Channelopathies: ion channel mutations that dictate human disease

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• Familial Hemiplegic migraines
• Episodic ataxia Type 2- neurological disorder
• Benign Familial Neonatal Convulsion- K channel problem
• Generalized epilepsy with febrile seizures--

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• Familial Hemiplegic migraines

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muations of the Ca channels. Pore mutation causes ataxia too/ non-pore mutation causes the migraines only

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• Episodic ataxia Type 2- neurological disorder

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disorder in which affected individuals suffer recurrent attacks of abnormal limb movements and severe ataxis.

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• Benign Familial Neonatal Convulsion- K channel problem

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Causing frequent seizures at birth and then gone.

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• Generalized epilepsy with febrile seizures

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Problem with Sodium channels causes paralysis and generalized epilepsy with febrile seizures.

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Synapsin I :

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staging vesicles for release.
Phosphorylation
by Ca 2+ /CAM
kinase releases
synapsin from
actin.