Lecture 4+5 Flashcards
What are gap junctional intercellular channels formed from?
connexins
What are oligo connexins?
connexins that make “reflexive” junctions to shorten pathway of diffusion (found in spatial buffering)
___ has the smallest single- channel conductance and pore size – perfect for electrical conductance.
Cx36
allow ionic current to flow passively from one neuron to another; very fast, bidirectional transmission
electrical synapses
What are the advantages of electrical synapses?
- rapid,synchronized communication between cells
- relatively fail-safe
What are the disadvantages of electrical synapses?
- difficult to modulate gating of channels
- can’t change the “sign”
Where are electrical synapses found?
- during early embryonic stages
- interneurons in the cerebral cortex, thalamus, cerebellum, etc.
- brainstem neurons – generate rhythmic electrical activity that underlies breathing
- retinal neurons (photoreceptors, bipolar cells, horizontal cells, amacrine cells, ganglion cells)
- “escape reflex” in many organisms
What happens when Cx36 is disabled/eliminated?
- loss of synchronous activity among interneurons
- retinal deficits (e.g., total night blindness)
- EEG abnormalities
- slower motor-coordination learning (Firsch et al., 2005)
- deficits in circadian behavior
- loss of ocular dominance plasticity
communication between neurons that involves a rapid release and diffusion of a chemical signal secreted from the presynaptic membrane of one cell
chemical synapse
site of NT release receptors release on presynaptic cell
active zone
site containing NT receptors on postsynaptic cell
postsynaptic density
space between synapse and dendrite
synaptic cleft
the theory that the neurotransmitter is released in multimolecular “packets” of a fixed size
quantal hypothesis
the theory that synaptic vesicles are the structural basis of quanta – they contain neurotransmitter, which they release by fusion with the presynaptic membrane
vesicle hypothesis
the theory that voltage-dependent calcium entry couples stimulation (i.e., the action potential) to secretion
calcium hypothesis
the theory that interactions between SNARE proteins on the vesicle and the presynaptic membrane, modulated by calcium, lead to vesicle fusion
SNARE hypothesis
spontaneous change in potential even in the absence of an action potential; same shape as EPP but smaller
MEPP (miniature end plate potential)
What are the characteristics of a MEPP?
- size declines with distance from NMJ -> arise at synapse
- disappear when nerve is removed -> come from nerve
- blocked by Ach inhibitors -> due to NT action
- correspond to ~5-10,000 molecules of ACh
How are MEPPs and EPPs related?
The EPP is made up of many MEPPs (i.e., quanta) released simultaneously
average number of vesicles released upon stimulation;
quantal content (M)
If a perturbation (drug, stimulation pattern, disease, etc.) affects quantal number, the effect is likely _____.
presynaptic
how many receptors does one vesicle activate (measured by EPP size)
Quantal size (Q)
If a perturbation (drug, stimulation pattern, disease, etc.) affects quantal size, the effect is likely ____.
postsynaptic
A presynaptic alteration will show _____ in MEPP amplitude but ____ in EPP/MEPP.
no change
change
A postsynaptic alteration will show ____ in MEPP amplitude but _____ in EPP/MEPP.
change
no change
There are _____ molecules of NT per vesicle.
~10,000
discharge of the contents of a single synaptic vesicle
quanta
What happens during the calcium hypothesis for neurotransmitter release?
1) An action potential arrives at presynaptic terminal and depolarizes it.
2) Voltage-gated calcium channels open.
3) Calcium enters the presynaptic terminal.
4) Calcium influx triggers fusion of synaptic vesicles. 5) Neurotransmitter is released.
What happens if Ca+2 is absent from the extracellular space?
no postsynaptic response; amount of NT released is sensitive to the exact amount of Ca2+ that enters the presynaptic terminal
What happens during the SNARE hypothesis of neurotransmitter release?
• Neurotransmitters are actively transported into synaptic vesicles (1)
• Vesicles cluster at the active zone (2), dock (3), and are primed (4) to ready
them for Ca2+-triggered fusion (5).
• After NT is released, vesicles are endocytosed (6) and recycled.
• Vesicles are refilled with NT directly (7) or after passing through an endosomal intermediate (8).
SNAREs found on synaptic vesicles
Synaptobrevin
SNAREs found on vesicle, acts as Ca2+ sensor
Synaptotagmin
SNAREs found on presynaptic plasma membrane
Syntaxin and SNAP-25
What happens during priming of SNARE NT release?
Prepare for rapid triggering of exocytosis
• vesicle must be primed and ready to fuse in <0.5 msec
• Ca2+ channel binds syntaxin
• synaptotagmin is the calcium sensor
• prepare for fusion: ATP
What happens during vesicle fusion of SNARE NT release?
- Ca2+-induced, fast neurotransmitter release
- released NTs diffuse across the synaptic cleft and interact with receptors in the post- synaptic membrane
____ affects SNARE proteins involved in vesicle fusion; impairs NT release.
Botulinum toxin (botox)
loss of voltage- gated calcium channels
Lambert-Eaton myasthenic syndrome
impaired vesicle recycling
Congenital myasthenic syndrome
What are the advantages of chemical synapses?
- can be modulated (at one of many steps)
* change signs by release of inhibitory neurotransmitter
What are the disadvantages of chemical synapses?
- multiple steps are required for NT release and receptor activation time delay
- directional(presynaptic –> postsynaptic only)
What are the major differences between electrical and chemical synapses?
electrical: gap junction channels composed of connexins, cytoplasmic continuity, flow of ions, 3.5 nm distance between pre- and postsynaptic membrane, brief or no delay, bidirectional transmission
chemical: presynaptic vesicles and postsynaptic receptors, no cytoplasmic continuity, chemical transmitters, 20-40 nm distance between pre- and postsynaptic membrane, 1-5 ms synaptic delay, unidirectional transmission
Botulism prefers a ___ pH, _______ environment. The toxin passes through bloodstream to reach ___ and cleaves ____. This results in _____ and _____. This is ____.
low anaerobic NMJ syntaxin and SNAP25 no ACh release no muscle contraction irreversible
Tetanus travels to ___, binds irreversibly, cleaves ____ to block release of ____ neurotransmitters
–> body cannot ____.
CNS
SNARES (synaptobrevin)
inhibitory
prevent muscle contraction
What are some symptoms of tetanus?
lockjaw, difficulty swallowing, continuous muscle spasms throughout the body, including breathing
Alpha- latrotoxin toxin affects what part of the NT release pathway?
promotes Ca2+-dependent vesicle fusion; promotes vesicle exocytosis instead of blocking it
receptors that let ions flow through; fast and direct; voltage- or -ligand gated
ionotropic
receptors that change metabolism; slow and indirect; G-protein coupled
metabotropic
Name the 7 small molecule NTs.
- acetylcholine
- dopamine
- GABA
- glycine
- glutamate
- norepinephrine
- serotonin
derived from larger proteins (up to 36aa); exclusively use GPCRs
neuropeptides
What is Dale’s rule?
all terminals of a neuron release the same neurotransmitter(s); very common to release both a small molecule and a neuropeptide (separate vesicles)
breaks down ACh in synaptic cleft; cleaves 5000 molecules/sec
acetylcholinesterase
___ is a ligand- gated ion channel for ACh
nicotinic acetylcholine receptor (nAChR)
component of venom from elapid snakes that blocks the acetylcholine receptor
alpha bungarotoxin
There are __ ACh binding sites per receptor. The receptors are ___ than voltage-gated channels and __ ion specific.
2
larger
less
What is the structure of nAChR?
• 5 subunits (a2, b, d, g)
• each subunit has 4 membrane-spanning
domains (TM1-TM4)
• TM2 lines the pore
• 3 rings of negatively charged amino acids around TM2: selects for cations
• poor selectivity compared to potassium or sodium channels: allows K+, Na+, and Ca2+
potential at which current flow through AChR channel is 0; inward and
outward currents are equal and opposite
reversal potential (Erev)
What ions flow through AChR
cation channel (K+, Na+, and some Ca2+)
What is Erev for AChR (which Eion)?
Erev for the AChR is not at the equilibrium potential of a single ion - lies between EK and ENa
In AChR, because ___ are similar, current depends on ____ for each ion.
permeabilities
driving force
When muscle is at rest and AChR opens, __ rushes in an very little __ rushes out, depolarization leads to __.
Na+
K+
EPSP (EPP)
ligand-gated ion channel open too long (i.e., too much neurotransmitter) -> channel closes
Desensitization
What is succinylcholine and how does it work?
muscle relaxant in surgery because it causes desensitization; succinylcholine not easily cleaved by acetylcholinesterase
Nearly all excitatory CNS neurons are ____. ___ is most common precursor – converted in presynaptic terminal; retrieved from synapse by transporters in both neuron and glia. Too much ___ can kill (__)
glutamatergic
Glutamine
glutamate
excitotoxicity
Glutamate has ionotropic receptors that are non-selective ___ channels. It also has metabotrpic receptors that activate ____.
cation
GPCRs
Glutamate binds to the ionotropic __ receptors, allows __ and ___ ions through; evoke EPSPs that are __ and ___.
AMPA sodium potassium large fast
Glutamate binds to the iontotropic ____ receptor, which allows flow of Ca2+ in addition to Na+ and K+. Increased Ca+2 can act as a ____. It evokes EPSPs that are ___ and ___.
NMDA
second messenger
slow
long-lasting
NMDA channels are blocked by __ in pore. Block is removed by ___; requires either multiple cells to fire or a single cell to fire repeatedly.
Mg2+
depolarization
NOTE: no Mg2+, no block – channel is always open
inhibitory NT that is everywhere (cortex, midbrain, etc.); most important inhibitory NT in brain
GABA
inhibitory NT that is in the spinal cord, brainstem, retina (evolutionarily older); low levels in other areas
Glycine
Inhibitory NT activate ligand-gated ion channel selective for __, which flows into the cell; cell becomes more __.
Cl-
hyper polarized
In metabotropic (GPCRs), NT binds receptor extracellular domain. Intracellular domain binds a set of 3 proteins – α,β,γ - together, called __. ___ is hydrolyzed– ___ splits off an binds to effector protein and activates/inactivates.
G proteins
GTP
α
Cyclic AMP (cAMP) is generated from ATP by ____. cAMP activates __, which can activate many proteins, including channels.
adenylyl cyclase
protein kinase A (PKA)
when a few molecules of NT can have a big effect
amplification
What are the advantages of GPCRs?
- amplification
- multiple effects on a single target
- multiple targets
The primary structures and NT involved in depression are?
hippocampus and prefrontal cortex
norepinephrine and serotonin
___ metabolizes serotonin, noradrenaline, and dopamine - removes them from use by the neuron.
___ are anti-depressants that prevent breakdown - more NT available for release
MAO
MAOIs
___ block serotonin and noradrenaline transporters (i.e., reuptake pumps). They have no effect on __. They are antagonists of multiple ___ and ___ along with ___ and ___ receptors, which leads to multiple side effects.
TCAs (tricyclic antidepressants) dopamine serotonin noradrenaline histamine acetylcholine
___ block re-absorption of serotonin - more available at synapses; can be extended/controlled release; generally fewer side effects
SSRIs (selective serotonin reuptake inhibitors)
Drug with the same concept as SSRIs but with noradrenaline instead of serotonin
SNRIs (selective noradrenaline reuptake inhibitors)
biochemical imbalance in serotonin/noradrenaline may underlie pathogenesis of depression
Monoaminergic hypothesis
Many sub-threshold synaptic inputs sum together in the soma
intergration
second of two closely spaced EPSPs is bigger than the first due to increased quantal content
facilitation
What is the residual calcium hypothesis of facilitation?
Ca2+ enters to trigger transmitter release, then removed; when 2nd stimulus is soon after 1st, not all Ca2+ has been removed from the initial pulse
smaller synaptic potentials with repetitive stimulation (often at high frequency) –> depletion of readily available vesicles and decreased quantal conten
depression
Excitatory synapses generally occur on __ or __. Inhibitory synapses closer to the __.
dendritic shafts
spines
axon initial segment
What factors affect synaptic integration?
- distance of synapse from initial segment; dendrites are leaky and signals attenuate with distance
- shunting inhibition: inhibitorysynapselocated between an excitatory synapse and soma can cause EPSP to attenuate to zero before reaching soma
- temporal and spatial summation: multiple synaptic potentials combine within one postsynaptic neuron
