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97 Cards in this Set

  • Front
  • Back
2 families of metabotropic receptors (229)
1. G-protein coupled receptors: activate ion channels to activate a GTP-binding protein that causes a second-messenger cascade

2. receptor tyrosine kinase: modulate ion channel activity indirectly by causing a phosphorylation reaction cascade.
subunits of G proteins (L1)
alpha and beta/gamma
the cAMP cycle (L1)
1. a transmitter binds to the extracellular portion of a beta-adrenergic receptor, causing a conformational change in the receptor.
2. The receptor can now bind the Gs protein, made up of the alpha and beta/gamma subunits attached to a GDP.
3. This causes GDP to be exchanged for GTP, which causes the dissociation of the alpha subunit from beta/gamma, which exposes the adenylyl cyclase binding site on alpha.
4. The alpha subunit binds to adenylyl cyclase, which activates it to make lots of cAMP.
5. While bound, the alpha subunit acts as a GTPase. Once GTP is converted to GDP + Pi, alpha dissociates from adenylyl cyclase (deactivating AC) and can once again bind with the beta/gamma subunits.
6. This cycle continues until the transmitter is no longer bound to the receptor.
cAMP pathway (fig. 13.5)
1. cAMP, produced by adenylyl cyclase, binds to 4 sites on the regulatory subunit of cAMP dependent protein kinase (PKA)
2. this causes the inactive, bound catalytic subunits to dissociate from the regulatory subunit, making the catalytic subunits active.
3. The catalytic subunits go on to phosphorylate a bunch of cellular proteins, which makes them active and causes a cellular response.
where (with what) is PKA involved? 3 things (L1)
1. channels
2. ion-gated channels
3. synaptic vesicle proteins
what is the amino acid sequence that gets phosphorylated by the catalytic subunits of PKA? (L1)

The serine is phosphorylated.
diacylglycerol-inositol triphosphate pathway (fig 13.7)
1. transmitter binds to receptor, which causes a conformational change and the activation of a G-protein
2. the alpha subunit associates with phospholipase C, activating it to cleave PIP2 into IP3 and DAG

IP3 is water soluable and diffuses through the cytoplasm to the IP3 receptor on the ER. This opens the receptor, which allows the release of Ca2+ from internal stores.

DAG is hydrophobic and remains in the membrane, where (along with membrane phospholipids), it activates protein kinase C, which is inactive unless it is brought to the membrane. PKC phosphorylates cellular proteins, causing a cellular response.
roles of Ca2+ in the cell (L2)
1. contraction of muscle
2. implicated in muscular dystrophy (how?)
arachidonic acid pathway (very briefly) (fig. 13.8)
1. transmitter causes receptor to activate a G protein. The beta/gamma subunit activates phospholipase A2 (PLA2)
2. PLA2 hydrolyzes PI in the plasma membrane, leading to release of arachidonic acid
tyrosine kinase pathway: (L2)

what is it activated by?
what is its mechanism?
activated by growth factors EGF, NGF, BDNF (ligands)

1. one of these growth factors bind to the extracellular domain of a tyr kinase receptor, which causes the tyrosine kinase receptors to dimerize.
2. this causes the intracellular kinase to be active: causes phosphorylation on tyrosine residues of the receptors themselves
3. this further activates the kinase, which can then phosphorylate other proteins
where are metabotropic receptors found within the cell? (L2)
either presynaptic, postsynaptic or around whole cell
example of how metabotropic receptors can modulate synaptic actions--pre-synaptic (L2)

fig. 13.10
can regulate potassium channels in the pre-synaptic cell by blocking them via phosphorylation

This causes the duration of the AP to increase, causing more synaptic release and a greater PSP.
example of how metabotropic receptors can modulate synaptic actions--post-synaptic (L2)

fig. 13.10
through the cAMP pathway, can keep open the ionotropic receptor allowing Na+ in, which allows a greater EPSP magnitude and AP.

also, modulation of resting voltage channels occurs, which can change threshold, space/time constants, and action potential duration
serotonin in Aplysia (fig 13.12)
a serotenergic interneuron makes modulatory synaptic connections on the cell body and axon of a sensory neuron that provides fast, glutamatergic connections to a motor neuron, mediating a gill-withdrawal reflex.

In this interneuron, serotonin binds to receptors and goes through the cAMP pathway, activating PKA, which phosphorylates S-type (resting) K channels, which closes them. This causes increased depolarization and a slow EPSP in sensory neurons. Due to the decreased membrane conductance (due to the closing of K channels), the voltage pulse is increased ala Ohm's law.
relationship between core dense vesicles and metabotropic receptors (L3)
the neuropeptides contained within the core dense vesicles activate metabotropic receptors
what kind of molecules are released at the active zone? (L3)
only neurotransmitters (neuropeptides aren't released at the active zone, but can be released anywhere within the neuron)
outline the freeze fracture experiment that dealt with exocytosis (L3)
at the NMJ

1. added voltage-gated potassium channel blocker to increase the probability of an AP.
2. used freeze-fracture technique and saw that the synaptic bouton is omega-shaped, which suggested that vesicles fuse with the membrane.
3 steps of exocytosis (L3)
1. fusion of synaptic vesicles with the presynaptic membrane
2. opening of fusion pore
3. complete dilation of the fusion pore and complete fusion of the vesicle with the plasma membrane
3 theories of fusion mechanisms (L3)
1. kiss and run
2. full fusion
3. bulk endocytosis
kiss-and-run fusion mechanism (L3)
Vesicle releases its contents and moves on --> NOT full fusion

dominant at low frequency stimulation
full fusion mechanism (L3)
dominant at high frequency stimulation, >10Hz
synapsin protein (L3, 270)
complexes with the cytoskeletal component of presynaptic neuron and synaptic vesicles to immobilize the vesicles

also a substrate for cAMP-dependent protein kinase and Ca2+/calmodulin dependent protein kinase
reserve pool (L3)
vesicles that are not mobile, tethered by synapsins
name the 5 steps in synaptic release (L3)
1. mobilization
2. trafficking/targeting
3. docking-priming
4. fusion
5. repair of membrane
synaptic release: mobilization

what is it? what protein is it controlled by? how does it work?(L3, fig 14.14)
triggers reserve vesicles to move to the active zone

controlled by synapsins (Ia, Ib, IIa, IIb)

1. Ca2+ enters the cell and eventually causes Ca2+/calmodulin-dependent kinase and PKA to phosphorylate Ia and Ib.

2. once they are phosphorylated, synapsin loses its affinity for the cytoskeleton and vesicles move into the active zone.
synaptic release: targeting

what is it? what protein is it controlled by? how does it work? (L3, fig 14.14)
targeting of vesicles to their release sites

controlled by proteins of the ras proto-oncogene family: Rab3a and Rab3c. Rab3a binds to GTP, and binds to synaptic vesicles. During targeting of vesicles in the active zone, Rab3a hydrolyzes its GTP to GDP (possibly makes reaction irreversible so that the vesicles must stay in the active zone).
synaptic release: docking-priming, fusion, and repair of membrane (L3)

what complex is involved and what does it contain? how does synaptic docking work?
the SNARES complex is involved. It contains syntaxins, SNAP25, RIM, munc13, munc18, etc.

The v-SNARE VAMP binds to the 2 t-SNARES (syntaxin and SNAP-25), promoting fusion of vesicle with membrane. Then, NSF and SNAP bind to the SNARE complex and disassemble it, using ATP. Allows for vesicle recycling.
VSNARES, what do they do? where are they found? (L3)
protein in vesicle membrane

bind to specific receptors in target molecules

example: VAMP (synaptobrevin)

found in nerve terminal
effect of tetanus on VAMP
tetanus cleaves VAMP, so that no complex forms and no synaptic release occurs.
types of botulinum toxin and what they do (L3)
type A: cleaves SNAP25
type B: cleaves VAMP
type C: cleaves syntaxin

essentially, prevents vesicles from docking to the membrane
synaptotagmin (272, L3)
inhibits exocytosis (NT release)
what is the interaction between VAMP, syntaxin, and SNAP25 like?
very, very stable (thus proteins NSF and SNAP must be available for recycling of vesicle)
3 steps in the formation of the NMJ (L4)
1. formation of selective connections between developing axons and their targets
2. differentiation of the axon's growth cones into a nerve terminal
3. differentiation of postsynaptic apparatus in the target cell.
why was the NMJ used to study synapse formation? (L4)
1. its large size and accessibility
2. contains a large # of receptors (ACh)
3. can use bungarotoxin to track receptor movement and to purify receptors (through specific binding)
bungarotoxin: what is it and what do we use it for? (L4)
binds irreversibly to ACh receptors at the NMJ

use it to track receptor movement at the NMJ and to purify receptors (through specific binding)
list the steps in synapse formation at the NMJ (fig 55.1)
1. myoblasts fuse to form a myotube
2. growth cone contacts the myotube
3. terminal accumulates synaptic vesicles and a basal lamina forms in the synaptic cleft
4. as the muscle matures, multiple axons converge on a single site
5. all axons but one are eliminated and the survivor matures
myoblast (L4)
undifferentiated muscle cell
what event of synapse formation does ACh help shape? (L4)
the early event (when myoblasts fuse into myotubes)
genes controlling the formation of ACh R subunits

when do ACh R subunits form? what activity do they have?
ACh R form when the myotube forms and is controlled by genes encoding the subunits alpha, beta, gamma, and delta

at this point, ACh R are functional and can produce EPSPs
ACh clustering and hot spots

what is the initial density of Ach R on the myotube?

differentiation of Ach R as NMJ matures(L4)
at first, ACh R are distributed uniformly across the myotube at ~1000/um^2 (except that some receptors form clusters on the myotube, which are called hot spots, but as development continues, the amont of receptors is highest around the synapse (10,000/um^2), lower in the perisynaptic area (10/um^2), and lowest in the extrasynaptic area
3 processes that effect the redistribution of ACh receptors (1092)
1. translocation of ACh R within the membrane from non-synaptic to synaptic regions
2. transcriptional activation of the expression of genes for the ACh R subunits in the few nuclei that lie directly beneath the postsynaptic membrane
3. repression of the expression of receptor unit genes in the nuclei of nonsynaptic regions.
experiment showing that nerves do not automatically go to hotspots in the myotube (L4)
1. cultured frog myoblasts, added nerves
2. observed where contacts were made by labelling myotubes with fluorescent bungarotoxin

Found that synapses formed randomly, proving that the idea of predisposition was incorrect.
so...if the idea of predisposition isn't correct, what is? (L4)
neurites seem to contact myotubes at random. Then, new ACh R form at sites of contact.

Pre-existing clusters that are stable in the absence of the nerve disperse once the synapse forms.
experiment that led to discovery of agrin (fig 55.6)
1. ACh R on cultured myotubes were labeled with bungarotoxin
2. added an extracellular matrix extract and clustering of synapses occurred

They found agrin in the extracellular extract and purified it.
structure of agrin

which type is involved in clustering? (L5)
large heparin-sulfate proteoglycan

synthesized by motor neurons

transported down and released from nerve terminals, where it is stably associated with basal lamina.

The Z+ type is involved in clustering.
how does agrin work? (L5)
binds to and activates MuSK, which triggers a cascade of intracellular reactions that result in clustering.
what is the agrin hypothesis and evidence to support it? (L5)
agrin hypothesis: agrin is a main nerve-derived organizer of postsynaptic differentiation at the NMJ.

1. postsynaptic differentiation is altered in agrin mutant mice
2. introduction of agrin into muscle cell elicits formation of a complete postsynaptic apparatus
3. although myotubes and Schwann cells express agrin, Z+ agrin can cause postsynaptic differentiation.
tell me about MuSK: what it does, its structure, etc. (L5)
the receptor for agrin

is a transmembrane receptor localized in the postsynaptic membrane and concentrated at the NMJ

in the absence of MuSK, no clustering of receptors occurs.

yet, MuSK and agrin are not the full story --> no crosslinking occurs between the two unless muscle cell extract is added
agrin hypothesis aside, what is the current view on the function of agrin? (L5)
it is only involved in maintenence of clustering
rapsyn: how was it isolated, what is known about it (L5)
isolated by virtue of its tight association with ACh R

in absence of rapsyn, no clustering occurs
relationship between agrin, MuSK, and rapsyn (L5, 1094)
1. agrin released from the nerve localizes MuSK to synaptic sites and also activates MuSK.
2. MuSK then stimulates ACh receptor clustering via its kinase activity (and thus affects rapsyn?) and plays a structural role in nucleating synapse assembly.
embryonic stages in mice as it relates to synapse formation (L5)
1. initiation of synapse formation (synaptogenesis): E12-E16
2. maturation: E16-2 wks postnatal
experiment with agrin, MuSK, rapsyn mouse mutants (fig. 55.6)
1. muscles were double labeled for ACh receptors and nerves. By birth, ACh R have formed beneath each nerve terminal.
in agrin mutant Z-/-: few clusters present
in MuSK mutant: NO clustering
in rapsyn mutant: NO clustering, [but ACh R levels are higher in the synaptic area than at the ends of myotubues, reflecting the preservation of synapse-specific transcription?]

something about HB9
what does neuregulin bind to? (L6)
ErbB kinase receptors (tyrosine kinases)
what are the 2 sources of neuregulin? (fig 55.7)
can come from the motor axon or are synthesized by muscle

the kind we're concerned about are expressed by motor neurons and secreted into the synaptic cleft
what were the circumstances under which neuregulin was isolated? (L6)
isolated in a search for neuronal factors that stimulate ACh R synthesis by myotubes
ErbB kinases (L6)
neuregulin receptors

transmembrane proteins, tyrosine kinases

highly concentrated at the NMJ
agrin causes ____ of receptors and neuregulin causes _____. (L6)
clustering, activation
experiment showing how agrin and neuregulin work (L6)
1. agrin was added to myotubes and they saw clustering of receptors, but no mRNA transcripts.
2. when neuregulin was added to myotubes, they saw a lot of mRNA transcripts, but no clustering.

Thus, agrin is involved in clustering, neuregulin in activating genes.
why can't we test the role of neuregulin in synapse formation? (L6)
because mutant mice that lack neuregulin or ErbB die at early embryonic stages (before muscles form). Thus, their synaptic phenotypes cannot be assessed.
experiment that knocked out Erb R (L6)
in the absence of ErbB, the results are mixed: although there are come neuromuscular defects, at least some of the transcriptional specialization of synaptic nuclei still occurred.

Thus, 2 different conclusions:
1. axonal neuregulin might act in parallel with agrin a. (agrin-->MuSK-->Ach) b. neuregulin-->activating

2. neuregulin might act primarily as a signal from axons to Schwann cells. In its absence, Schwann cells are absent, meaning the nerve terminal is compromised, which can affect the release of agrin.
relationship between neuregulin and Schwann cells (L6)
when neuregulin is absent, Schwann cells are absent
synaptic maturation in mice (L6)
E13: receptors are diffuse in the myotube
E14: some clustering
E17: clustering of receptors
birth: many more receptors in cluster (plaque)
P5: perforation occurs
P10: differentiation of branches
P30: branches differentiated
2 years (adult): starts to degrade? synapse weakens
tell me about plaque formation, branching, fold formation (L7)
occurs late in embryogenesis (birth).

the borders of the cluster sharpen, the length decreases, and ACh density inreases.

after birth, the plaque becomes perforated, eventually forming a pretzel-like array of branches.

branches expand in an intercalary fashion as the muscle grows

as these changes occur, the plaque is invaginated to form folds
when does the NMJ become functional (L7)
before birth

neonates are completely dependent on NMJ transmission for survival
when does synapse elimination occur

time frame
during early post-natal life

P0: muscle fibers innervated by multiple neurons, which are intermingled with each other.

P5: terminal segregation of neurons occurs (they begin to separate)

P10: branch withdrawal begins --> so that only one nerve innervates a muscle fiber

2 weeks: synapse elimination complete
what is "sprouting"? (L7)
I'm not entirely sure, but I do know that it is a sign of bad post-synaptic activity

If I had to guess, I'd say it is when synapse elimination does not happen properly and multiple axons begin growing on a myotube.
synapse elimination (fig 55.11)
as the NMJ develops, each myotube becomes innervated by several motor axons at a common synaptic site. After birth, all terminals but one withdraw from each site and the survivor grows.

This elimination occurs without any overall loss of axons. Axons that "lose" at some muscle fibers "win" at others.
axotomy (L8)
when a nerve is cut, it reinnervates slowly because the synapse forms in a new place

when it is crushed, it reinnervates quickly because the synapse reforms in the same location

causes myelin to degenerate, cell body to undergo chromatolytic reaction
Wallerian degeneration (1108)
when the myelin sheath (which requires axonal contact for its maintenence) becomes fragmented and is eventually enveloped, along with axonal debris by phagocytic cells.

this happens to the distal portion of the severed (pre-synaptic) neuron
chromatolytic reaction (1108)
the cell body swells, nucleus moves to an eccentric (ancocentric) position, and the rough ER becomes fragmented. Metabolic changes also occur.

Changes are reversible if regeneration is successful; otherwise, the cell may die.
how does axotomy affect the input cell?

also, chain reactions in pre- and post- syn cells(1108)
synaptic stripping may occur

antero- and retrograde degeneration can occur: a denervated neuron that becomes severly atrophic can fail to activate its target, which then becomes atrophic as well. Same with synaptic stripping.
synaptic stripping (1108)
when synaptic terminals withdraw from the neuronal cell bodies of chromatolytic neurons and are replaced by the processes of glial cells.

depresses synaptic function and can impair recovery of function
reactive astrocyes (1109)
glial cells in the CNS that participate in synaptic stripping in response to Wallerian degeneration and contribute to the formation of a glial scar

immune cells can also be recruited to form a scar
proximal stump

distal stump
proximal stump is the part of the severed neuron that contains the cell body

distal stump is the part that is separated from the cell body
axonal sprouts, and mechanism (1109)
Axonal sprouts grow from the proximal stump, enter the distal stump, and grow toward the nerve's end-organs.

chemotropic factors secreted by Schwann cells attract axons to the distal stump, adhesive molecules within the distal stump promote axon growth along cell membranes, and inhibitory molecules in the perineurum prevent the regenerating axons from going astray.
compare regeneration in the PNS and CNS (1110)
All three branches of the PNS can regenerate (though sometimes fine motor skills are not as good as before). Regeneration is poor without laminin (protein in the basal lamina), which is plentiful in PNS, but not in CNS.

In the CNS, little regeneration can occur
CNS regeneration and inhibitory factors (1111)
was proposed that both the PNS and CNS contain a large amount of growth-promoting elements (laminins, tropic molecules), but the CNS contained inhibitory factors, like central myelin. Myelin 35 inhibits outgrowth of neurons in CNS.
CNS regeneration and secondary changes in cell environment (1111)
A number of events are prominent following brain injury: astrocyte proliferation, activation of microglia, scar formation, inflammation, invasion by immune cells. These changes may render an otherwise permissible environment inhospitable.
experiment, Viktor Hamburger (L9)
showed that the number of sensory neurons in dorsal root ganglion of amphibian embryos was increased by transplantation of an additional limb bud into the target field

thus, the target influences proliferation and differentiation of sensory neurons.
experiment with chick embryos, muscle buds (L9, fig 53.11)
she removed a developing limb bud and noticed that while motor neurons were generated at normal levels, later in development, few motor neurons remain on the side of the spinal cord on the side of the missing limb (# of motor neurons is 50% as much).

When she transplanted an extra limb bud onto the embryo, she saw that it reduces the extent of naturally occuring cell death so that 75% of motor neurons survive on the side that has 2 limb buds.

When she blocked muscle activity by curare, it reduces extent of motor neuron death so that 75% of neurons survive on both sides.

thus: size and muscle target are critical for survival of spinal motor neurons. Led to the neurotropic factor hypothesis.
neurotrophic factor hypthothesis (L9)
neurotropic factors are released by the source (muscle, for instance). Those neurons that take up the NF live and those that don't, die.

another perspective on synapse elimination
the first and second neurotropic factors introduced

and others(L9)
first: nerve growth factor (NGF)
second: BDNF

then, neurotrophin 3, 4/5
explain why the chick embryos treated with curare had less cell death than normal (L9)
survival of motor neurons depends on muscle activity, so in the absence of post-synaptic activity (by using curare, for example), cell death is prevented and survival of motor neurons is enhanced.

electrical activity in neurons themselves is required for appropriate response to NFs.
explain how activity can control production of NFs (L9, 1055)
activity in the target cell could inhibit production of NF. Because the supply of NF is thought to be limited, any reduction in the supply would lead to a greater degree of neuronal death.

And the thing about the chick embryos: if there is no electrical activity (due to curare), neurons cannot respond correctly to NFs.
2 classes of neurotrophic factors (L9)
1. Trks (tropomyosin receptor kinases): TrkA, B, C. NFG binds preferably to trkA. BDNF and neurotroph 4/5 bind to trkB. Neurotroph 3 binds to trkC, but specificity is not absolute)

2. p75: all neurotrophins bind to this, but affinity for it is very low
experiment with sympathetic neurons in the presence of NGF (L9)
when NGF was added to sympathetic neurons, the neuron grew like crazy. When it was not added, no growth occured.
experiment with pyramidal neurons with BDNF and APV (L9)
when BDNF was added to pyramidal neurons, the neuron grew like crazy. When BDNF + APV were added, no growth occured, showing that NMDA R are involved in neurogenesis somehow.
trk receptors: structure (L10)
transmembrane glycoproteins

tyrosine kinases with extracellular ligand binding domain containing multiple repeats, leucine-rich motifs, 2 cysteine clusters, 2 immunoglobin-like domains and a single transmembrane domain.

each trk receptor binds a ligand through a specific sequence.
what does activation of trk receptors depend upon? (L10)
dimerization of receptors, a process initiated by the binding of the ligand. This leads to the activation of different signaling pathways through recruitment of various adaptor molecules.
what happens to the tyrosine residues on the trk? (L10)
they become phosphorylated and recruit PLC-gamma, which catalyzes the cleavage of the substrate of PIP2--> IP3 and DAG, leading to release of Ca2+ from internal stores.
NGF (L10)



NGF: a NF that controls sensory neurons of the dorsal root ganglia

BDNF: control mechanoreceptors on Merkel cells

NT4/5: control deep-hair cell

NT3: control many dorsal root ganglia neurons, early development.
apoptosis: why is it important? (L10)
an important mechanism involved in development and homeostasis in adult tissue.

important because apoptosis can remove infected, transformed, or damaged cells
3 things that characterize apoptosis (L10)
1. fragmentation of the cell into membrane-bound bodies
2. nuclear and cytoplasmic condensation
3. endolytic cleavage of DNA into small oligo fragments. The cells on these fragments are then phagocytosed by macrophages.
3 examples of how apoptosis is needed for proper development (L10)
1. resorption of the tadpole tail at the time of metamorphesis.
2. formation of fingers and toes in fetus
3. synapse elimination
3 things than can trigger apoptosis (L10)
1. cell surface receptors
2. signal rising within the cell
3. dangerous reactive oxygen species like H2O2 or hydroxy radicals
apoptosis proteins in c. elegans and vertebrates

relation to NFs(L10)
ced9 protein acts upstream of and inhibits activity of ced4, which is responsible for activation of ced3. activation of ced3 results in the cleavage of protein substrates and results in cell death.

In vertebrates, BCl2 (ced9) inhibits Apaf-1 (ced4) which activates caspase (ced3) and leads to cell death.

If NFs bind, it blocks Apaf-1, which means that cells survive