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MCBM exam 2 > synaptic transmission > Flashcards

synaptic transmission Flashcards

1
Q

vesicular docking and fusion involves?

A
  • interactions between synaptobrevin (in the vesicle membrane) and syntax in (in the plasma membrane) –> come together to form a SNARE complex –>facilitates exocytosis and membrane fusion
  • Ca2+ triggers the vesicular fusion to terminal membrane and exocytosis

-vesicle buds off from endosome (filled with NT)

active zones contain high levels of voltage-gated Ca2+ channels, fusion and docking proteins. when AP arrives–> influx of Ca2+ –> stimulate vesicles to dock and prepare for exocytosis into the synaptic cleft.

spent vesicles coated with clathrin, undergo endocytosis and recycled back into endosome inside the cell.

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2
Q

what triggers NT release?

A

axon terminal depolarization activated voltage gated Ca2+ channels that stimulate the release of NT sufficient for a postsynaptic response

experiments?
need Ca2+ before depolarizing to get a response
Mg 2+ added before Ca2+ can block the response

depolarization without Ca2+==> no post synaptic response

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3
Q

Type I synapses

A

excitatory (asymmetric) synapses–> will depolarize

widee synaptic cleft (30-40nm) and active zone (1-2 micrometers)

Vesicles clustered around dense projections (area above the terminal membrane)

Well developed postsynaptic density:
a lot of receptors for the excitatory NT
lot of scaffolding proteins
and signal transduction (Ca2+, calmodulin, protein kinase)

ex: glutamate in neuromuscular junction–> excitatory

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4
Q

Type II synapses

A

Inhibitory (symmetric) synapses–> decrease likelihood of postsynaptic depolarization

More narrow synaptic cleft (20nm) & active zone ( inhibitory

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5
Q

En passant (nondirected synapses)

A

Often observed in the post ganglionic autonomic nervous system neurons (SNS and PNS)
Varicose swellings interspersed along length of axon terminal serve as sites of neurotransmitter release
Greater separation between varicosity & postsynaptic membrane (400 nm)
No postsynaptic specialization–> regulation by the presynaptic elements –> slower and more diffuse onset of response

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6
Q

Criteria to be a neurotransmitter

A
  1. Neuronal biosynthesis (neuron has to make it)
  2. Localized to axon terminal, released in response to appropriate stimuli and in amounts that trigger a postsynaptic response
  3. Postsynaptic effect mimicked by exogenous application (without stimulus, but added NT–> still get response)
  4. Rapid termination of action (uptake or degradation)
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7
Q

Catecholamine biosynthesis (which product, enzymes, cofactors, location)

A

dopamine, norepi and eli from phenylalanine precursor

phenylalanine–> tyrosine

enzyme: phenylalanine hydroxylase
* REQUIRES tetrahydrobiopterin cofactor

tyrosine –> dopa (enz: tyrosine hydroxylase)
*REQUIRES tetrahydrobiopterin cofactor

dopa–> domamine (enz: dope decarboxylase pyrodoxial phosphate)

dopamine–> norepi (enz: dopamine beta hydroxylase)
*occurs within the synaptic vesicle

norepi–> epi (enz: phenylethanolamine-N-methyltransferase)
*in brainstem and adrenal cortical cells ONLY

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8
Q

indoleamine biosynthesis

A

tryptophan–> 5-hydroxytryptophan (5-HTP) (by tryptophan hydroxylase)

–>Seratonin (5-hydroxytryptamine (5-HT)) (by 5-HT decarboxylase)

seratonin in the gut and in dorsal raphe in the brain (regulation of mood and arousal)

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9
Q

histamine biosynthesis

A

histadine–> histamine (enz: histadine decarboxylase)

usually in posterior hypothalamus
regulate homeostasis

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10
Q

Amino acid NT biosynthesis

A
  1. glutamate
    Reductive amination of α-ketoglutarate (from Citric acid cycle) to form glutamate
    predominantly excitatory in the CNS
    found in large quantities in the CNS
    into synaptic vesicles by BPN 1 (transporter)
  2. GABA
    Decarboxylation of glutamate to form GABA
    predominantly inhibitory in the CNS
  3. Glycine
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11
Q

Neuropeptide transmitters

A

Derived from posttranslational modification of peptide precursors–> A LOT!

Examples
β-endorphin derived from proopiomelanocortin
Somatostatin derived from preprosomatostatin

Precursor: prepropeptide molecule
can have several neuropeptides.

Dibasic residues serve as cleavage sites.
serve as the N or C termini for bioactive peptides.

Whether expressed or not is based on post translational proteolytic cleavage

ACTH=important intermediary –> stimulates cortex to produce cortisol in anterior Pituitary

Hypothalamus=proteases will break ACTH into alpha-MSH (regulation of energy balance) and CLIP

beta-LPH also divided to form gamma-LPH and beta-endorphin

Combinations of NT can be formed by one precursor
expression depends on the array of proteases in the cells and tissues
tightly regulated tissue specific process.

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12
Q

Acetylcholine biosynthesis

A

Synthesized by choline acetyl-transferase (CAT)
(rxn: choline +AcCoA–> CoA+ACh)
Transported into vesicles via VAChT

in brain and neuromuscular junctions

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13
Q

G-protein

A

Guanosine nucleotide binding protein comprising α, β & γ subunits
α subunits possess GTPase activity
Transmitter binding triggers nucleotide exchange and dissociation of α subunit
-without ligand, GDP is bound to the alpha subunit.
-once NT is bound, GDP–>GTP and alpha is dislocated from the beta-gamma subunit

5 G protein families: Gs, Gi/o, Gt, Gq & G13

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14
Q

Dopamine receptors and interactions

A

D1 and D5 receptors interact with Gs–> stimulate adenylyl cyclase, cAMP and PKA

D2, D3, and D4 receptors interact with Gi/o which: inhibits adenylyl cyclase, cAMP formation, and PKA (activates K+ channels and inhibits Ca2+ channels)

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15
Q

Norepinephrine and epinephrine receptors and interactions

A

Interact with two subtypes of α receptor and three subtypes of β receptor

α1 receptors interact with Gq that activates phospholipase C (PLC)
PLC forms diacylglycerol (DAG) and inositol triphosphate (IP3) from phosphatidyl inositol bisphosphate
DAG activates protein kinase C
IP3 mobilizes intracellular stores of Ca2+

α2 receptors couple to Gi/o
decrease adenylyl cyclase –> inhibit Ca2+ influx

β1-3 receptors couple to Gs
increase adenylyl cyclase and increase PKA dependent phosphorylation

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16
Q

Serotonin (5-HT) Receptors

A

Numerous 5-HT receptor subtypes
5-HT1 receptors couple to Gi/o
inhibit AC–> decrease cAMP-> decrease PKA –> open K+ channels, decrease Ca2+ influx
5-HT2 receptors couple to Gq
The 5-HT3 receptor is a ligand-gated ion channel (like glutamate receptors)

17
Q

histamine receptors

A

H1 receptors couple to Gq
H2 receptors couple to Gs
H3 receptors couple to Gi/o

18
Q

Glutamate receptors

A

Majority are ionotropic receptors (ligand-gated ion channels)
Three subtypes of ionotropic glutamate receptors:
1. N-methyl-D-aspartate (NMDA) receptors
2. α-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors
3. Kainate receptors

19
Q

NMDA receptor

A 
Two primary subunits (NR1 & NR2)
Each subunit has:
Extracellular N-terminus
Intracellular C-terminus
Three transmembrane domains
Pore-forming loop (TM2)

Activation of the NMDA receptor:
Increases Na+ & Ca2+ influx
Increases K+ efflux
*Glycine requirement (positive allosteric modulator)
Mg2+ channel block
-rest, Mg2+ in the pore and glutamate ineffective
-depolarized==> Mg2+ kicked out of pore–> allows the movement of ions and depolarization of membrane potential

*PCP and ketamine=non competitive inhibitors (open channel blocker)
enter the pore in open state and produce noncompetitive inhibition

20
Q

AMPA and Kainate Receptors

A

Four AMPA receptor subunits (GluR1-4)
Five kainate receptor subunits (Glu5-7, KA1, KA2)

Structural characteristics similar to NMDA receptor subunits
The TM2 domain contains the Q/R site which Determines Ca2+ permeability of AMPA receptors
• Exchange of arginine for glutamate during mRNA processing at the Q/R site will render GluR2 impermeable to calcium.

o The N-terminal S1 domain, along with S2 domain linking the TM3 and TM4 domains, are critical for glutamate binding.

21
Q

GABA receptors and glycine receptor

A

GABA A receptor:
Pentameric ligand-gated Cl- channel
Comprises α, β, γ, δ & ε subunits
Numerous allosteric modulatory sites that alter channel function
throughout brain and spinal core and NS of the gut
GABA A bound–> open–> Cl- into cell–> hyper polarize/inhibitory response
o Benzodiozepines, barbiturates, alcohol and neurosteroids can all potentiate this receptor thru positive allosteric modification of the GABAA receptor.

GABA C receptor
Also a pentameric ligand-gated Cl- channel–> leads to hyper polarization and inhibition
Different arrangements of three ρ subunits

GABA B recptor
Metabotropic receptor that couples to Gi/o

Glycine receptor
ligand-gated Cl- channel
posy synaptic neurons in brain stem and spinal neurons
pentamer of alpha and beta subunits. GABA binds–>inhibits

22
Q

Muscarinic acetylcholine receptor

A

Interacts with two subtypes: muscarinic & nicotinic
Muscarinic acetylcholine receptors:

Five different subtypes (M1-M5)
M1, M3 (gut) & M5 couple to Gq
M2 (heart) & M4 (gut) couple to Gi/o

23
Q

nicotinic acetylcholine receptor

A

Nicotinic acetylcholine receptor:
brain and autonomic ganglia
pentameric ligand-gated mixed cation channel
Pentameric arrangement of α1, β, δ, ε & γ subunits
(epsilon in adults or gamma in embryonic tissue)
pore lining =M2 domain
Large N-terminus in the extra cellular matrix
Four membrane-spanning domains (M1-M4) in each of the 5 subunits
Short C-terminus in the extracellular matrix
Interacts with a number of intracellular scaffolding proteins
–>Rapsyn–> promotes the insertion of nicotinic receptor in the plasma membrane and stabilizes it there.

The acetylcholine binding site
The binding of two acetylcholine molecules required for full receptor activation
Involves N-terminal interactions between the α1 & δ subunits, and the α1 & γ (or ε) subunits
Critical residues
Y93, Y190, Y198, C192, C193 & W149 on the α1 subunit
Negatively charged residues on the δ & γ (or ε) subunits help stabilize the positively charged ACh molecule

5 M2 domains form 4 rings of negative charge to determine absolute and relative ion selectivity
extracellular ring = Na+ selectivity for influx (absolute)
intracellular ring =K+ efflux (absolute)
intermediate ring= determines the relative rate of ion transport
relative filter for ion transport
central ring

Coformational change–>Na+ inf and K+ out

Collective response is large
end plate potential =60-70 mV

activation of the nicotinic ACh receptor leads to:
Suprathreshold depolarization of the postsynaptic membrane
Activation of voltage-gated Na+ & Ca2+ channels (excitation/contraction coupling)
Action potential formation
Muscular contraction
–> resembles the fast EPSP (reverses polarity at 0mV, complete inactivation w/in 100 msec)

Multinodal distribution with .4 mV in between
sometimes spontaneous without stimulation
 mini-EPSPs in the absence of extracellular Ca2+  response of a single quantum of NT
Spontaneous could occur sporadically but only a few NT

A single quantum can depolarize the post synaptic membrane .4 mV
given a normal EPSP, or end plate potential (60-70 mV) can get idea of how many quantum are released

24
Q

Fast IPSP

A

Arises from the activation of ligand-gated Cl- channels
e.g., GABA (A or C) & glycine receptors
At rest, fast IPSP produces transient
Cl- normally flows into the cell–>hyperpolarization of the postsynaptic membrane
Reverses polarity at ECl
full activation=very fast
complete inactivation within 100msec

ECl=-60mV
at a Vm of -70–> Cl- channel opening will have a depolarizing effect

IPSPs used for the inhibition of antagonist muscles when an agonist is contracting by renshaw cells (inhibitory interneurons of the spinal cord)

25
Q

slow IPSP

A

Arises from the opening of a K+ channel modulated by Gi/o protein-coupled receptors
e.g., dopamine D2, 5HT1, α2 adrenergic & μ-opioid receptors
Channel modulation occurs via direct interactions with the βγ complex
results in a hyperpolarization more prolonged than the fast IPSP
Reverses polarity at EK

Few seconds to reach peak
full decay can be up to minutes
Dependent on the time constant intrinsic to the postsynaptic cell

26
Q

fast EPSP

A

Arises from the activation of ligand-gated mixed cation channels
e.g., AMPA & NMDA receptors (glutamate activates) or 5HT3
At rest, fast EPSP produces transient depolarization of the postsynaptic membrane
Reverses polarity at 0 mV, in between ECa, ENa & EK

NMDA = more sluggish, and blocked by Mg under resting conditions
at rest, only AMPA is activated. as depolarizes, Mg2+ removed from NMDA and this is also activated leading to further depolarization

*long-term potentiation
AMPA receptor-mediated depolarization relieves Mg2+ block of the NMDA receptor
Long-lasting NMDA receptor-mediated Ca2+ influx leads to synaptic adaptations that include:
protein phosphorylation
Retrograde messenger formation
More efficient glutamate release
Potentiation of the AMPA receptor-mediated fast EPSP
Cellular learning
==> increase synaptic strength from pre and post synaptic membranes=learning

27
Q

late, slow EPSP

A

Arises from the closing of a passive K+ channel modulated by Gq protein-coupled receptors
e.g., muscarinic M1, 3, 5 receptors, gonadotropin-releasing hormone (GnRH) receptors

Activation–> activate PKC–>phosphorylate a leak channel, closing the leak channel–>decrease K+ efflux–> depolarization for longer

Channel modulation occurs indirectly via channel phosphorylation
results in a long-lasting depolarization
Reverses polarity at EK

activate =up to 1 minute
complete deactivation =up to 10 minutes
Slow EPSP=long lasting changes in post symnaptic excitability

28
Q

pre-synaptic inhibition

A

Occurs at axo-axonic synapses
Neurotransmitter released from the upstream terminal decreases release from the a downstream neuron
Arises from the activation of Gi/o-coupled receptors that:
potentiate (increase) K+ currents and attenuate (decrease) Ca2+ currents

29
Q

Presynaptic facilitation

A

Occurs at axo-axonic synapses
Neurotransmitter released from the upstream terminal increases release from the other (downstream neuron)
Arises from the activation of Gs-coupled receptors that:
increase N-type Ca2+ currents into the nerve terminal
increase of duration of AP at nerve terminal–> increase in response

30
Q

catecholamine termination

A

(dopamine, serotonin, histamine)
Occurs through a combination of reuptake & metabolism
Metabolism via extracellular catechol-O-methyl transferase (in post synaptic neurons and glial cells) & mitochondrial monoamine oxidase (after monoamine NT transporter reuptake)
Reuptake via a monoamine neurotransmitter transporter
Requires co-transport of Na+ and Cl-

metabolites conjugated and excreted

31
Q

serotonin termination

A

• Occurs through a combination of reuptake & metabolism
• Reuptake via a monoamine neurotransmitter transporter
o Requires co-transport of Na+ and Cl-
• Metabolism via mitochondrial monoamine oxidase to form 5-hydroxyindoleacetic acid (5-HIAA).
• May also be converted to melatonin (in pineal gland) or conjugated

32
Q

histamine termination

A

• Occurs through a combination of reuptake & metabolism
• Reuptake via a monoamine neurotransmitter transporter
o Requires co-transport of Na+ and Cl-
• Metabolism via histamine-N-methyltransferase.
o Converts histamine to methylhistamine
• Further modified by MAO to yield methylimidazole acetic acid.

33
Q

Glutamate termination

A

• Removed from synaptic cleft via Na+-dependent glutamate transporter which is tied to Na+/K+ ATPase activity.

34
Q

GABA & glycine termination

A

Removed via active transport reuptake
Requires co-transport of Na+ and Cl-
GABA deaminated by GABA transaminase to succinic semialdehyde.

35
Q

neuropeptide transmitter termination

A

rapid termination due to proteolytic cleavage into smaller peptide fragments

36
Q

acetylcholine termination

A

rapid due to hydrolysis via acetylcholingesterase nto choline and acetate

MCBM exam 2 (11 decks)

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