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85 Cards in this Set

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  • Back
Gap junction channel is built from...
six identical subunits called CONNEXINS
Gap junction channels allow movement of what?
allows current to flow directly from one cell to the next

allows passage of small molecules (cAMP, Ca2+ that have signalling capabilities)
When/where are GAP JUNCTIONS most commonly found?
more common durinv development (rare in the adult nervous system)

Found in some groups of neurons that need to fire synchronously (e.g., brainstem respiratory neurons)
What regulates expression of the CONNEXINS that make up gap junctions
e.g. by steroid hormones
Permeability of GAP JUNCTIONS is regulated by:
second messengers
pH
and Ca2+
mutations in the genes encoding different connexins are believed to underlie what diseases?
1. CONGENITAL RECESSIVE NONSYNDROMIC DEAFNESS
and PROGRESSIVE DOMINANT DEAFNESS

2. CHARCOT MARIE TOOTH (CMT disease)
Connexin mutations can cause deafness because
loss of connexin expression (and therefore gap junctions) results in changes in K+ distribution in the COCHLEA and therefore...

changes the Vrest of cochlear haircells
mutations in what gene may account for 10% of all congenital hearing loss
connexin 26
Charcot Marie Tooth (CMT) disease
most common hereditary peripheral neuropathy (X linked form assoc. w/ Cx32)

characterized by diminished conduction of both MOTOR AND SENSORY axons

mutation results in the loss of gap junctions between overlaying intracellular loops of schwann cells

resulting in demyelination mainly in paranodal regions
loss of gap junctions between overlaying loops of Schwann cells underlies what disease?
Charcot Marie Tooth disease

characterized by diminished conduction of both: MOTOR and SENSORY axons
Fundamental properties of chemical synaptic transmission
1. NEUROTRANSMITTER stored in PRESYNAPTIC VESICLES
2. EXOCYTOSIS of presynaptic vesicles requires INFLUX of Ca2+ ions upon depolarization
3. Specific cognate receptors for each neurotransmitter in postsynaptic membrane
4. Neurotransmitter release and opening of the postsynaptic receptors is very vast
5. variety of mechanisms terminate action of neurotransmitters
what is required for exocytosis of presynpatic vesicles?
influx of Ca2+ ions upon depolarization
how long does it take for an action potential to travel from a presynaptic nerve terminal through the post-synaptic receptor?
~500 microseconds

due to fast release of neurotransmitter and opening of postsynaptic receptors
specificity of chemical transmission is conferred by
specific cognate receptors for each neurotransmitter in postsynaptic membrane
bulk of communication in the nervous system is...
chemical in nature
Sequence of events in neurotransmitter release
1. Depolarization (by action potential) opens voltage-gated Ca2+ channels in presynaptic terminal
2. Ca influx facilitates Ca-dependent exocytosis of neurotransmitter
3. Activation of cognate post-synaptic receptors by neurotransmitter binding
4. Termination by uptake, diffusion or hydrolysis
2 major classes of neurotransmitters
1. SMALL MOLECULES: biogenic amines (dopamine, norepi, epi, 5-HT, histamine), gultamate, GABA, glycine, ACh
2. LARGER NEUROPEPTIDES and NEUROHORMONES: over 50 id'd.. eg: opoids cannabanoids, substance P, vasopressin, oxytocin
2 major classes of neurotransmitter receptors
1. IONOTROPIC RECEPTORS: ligand-gated ion channels (time range ~ msec)
2. METABOTROPIC NEUROTRANSMITTER RECEPTORS: G protein-coupled and activation of 2nd messenger signalling pathways (time scale :msec to minutes or longer)
IONOTROPIC RECEPTORS
type of receptor:
time range:
ligand-gated ion channels

time range: msec
METABOTROPIC NEUROTRANSMITTER RECEPTORS
time range:
G protein-coupled
and activation of 2nd messenger signalling pathways

time scale: msec to minutes or longer
Examples of small molecule neurotransmitters
biogenic amines (dopamine, norepi, epi, 5-HT, histamine)
glutamate
GABA
glycine
ACh
Purines
Examples of larger neuropeptide and neurohormone neurotransmitters
over 50 id'd

opioids
cannabinoids
substance P
major inhibitory neurotransmitter in the brain
GABA (smalle molecule neurotransmitter)
what determines whether chemical transmission is inhibitory or excitatory?
determined by neurotransmitter receptors (which are inhibitory or excitatory)

neurotransmitters are NOT
Depolarization
lessening of membrane potential (eg. from -70 to -40 mV)
Hyperpolarization
increasing of membrane potential (e.g., from -60 to -90 mV)
EPSP/EPSC
excitatory postsynaptic potential/current
IPSP/IPSC
inhibitory postsynaptic potential/current
EPP
specialized neuromuscular excitatory synaptic potential END PLATE POTENTIAL
Excitation:
change in Vm that makes it more likely that Vm will exceed the threshold for generating an action potential (depolarization)
Inhibitions
change in Vm that makes it less likely that Vm will exceed the threshold for generating an action potential (many times hyperpolarization but does not have to be)
nicotinic acetylcholine receptors
(skeletal muscle and neuronal) are:
what type of receptors?
relay what type of signal?
Ionotropic Receptors

EXCITATORY
glutamate receptors (NMDA and AMPA)

receptor type?
signal type?
Ionotropic Receptor

EXCITATORY
(?mediate fast inhibition)
Purinergic receptors (bind adenosine or ATP)
receptor type?
signal type?
Ionotropic Receptor

EXCITATORY
GABAa receptors
found where?
receptor type?
signal type?
found mainly in brain
IONOTROPIC receptors
Inhibitory
**excitatory in dvpg brain and adult neurons after injury
Glycine receptors
found where?
receptor type?
signal type?
mainly expressed in spinal cord
IONOTROPIC receptors
Inhibitory
**excitatory in dvpg brain and adult neurons after injury
5-HT3 class of serotonin receptors
receptor type?
signal type?
IONOTROPIC
Excitatory
examples of compounds that can activate both ionotropic and metabotropic receptors
GABA
glutamate
serotonin
ATP
ACh
muscarinic ACh receptor is what kind of receptor?
metabotropic receptor
nicotinic ACh receptor is what kind of receptor
ionotropic (excitatory) receptor
(Neuronal and skeletal muscle0
GABAb receptor is what kind of receptor?
metabotropic
what kind of receptors are GABAa and GABAc?
ionotropic
inhibitory
Glutamate receptors that are
a) ioniotropic
b) metabotropic
a) NMDA
AMPA
Kainate
b) ACPD
which class of 5-HT receptor is ionotropic?
5-HT 3
neurons in the CNS receive about how many synapses?
tens of thousands

purkinje cell dendrites covered with presynpatic terminals (eg from granule cells)
neuromuscular junction involves what type of fibers?
involves fast twich fibers
each postsynaptic muscle fiber is innervated by...
a single motor neuron axon at a single well-define postsynaptic site
how efficacious is synaptic transmission at NMJs?
VERY HIGH efficacy
~1:1 safety factor (i.e. each action potential in the presynaptic cell gives rise to an action potential in the postsynaptic cell
Multiple muscle fibers can receive synaptic input from the same
neuron
Active Zones of NMJ
site of neurotransmitter release in presynaptic membrane of NMJ
where are vesicles found in NMJs
docked at active zones via:
-protein complexes between vesicle and plasma membranes and..
-association with cytoskeleton in the presynaptic terminal
vesicles at nmp contain what as the primary neurotransmitter?
ACh
What is required for exocytosis triggered by action potentials
Ca influx (via Voltage dependent Ca channels)

opened by depolarization from invading action potential

allows vesicles to fuse to membrane and exocytose neurotransmitter
Where are Ca channels found in nmj
localized to active zones
At nmj

Eca is greater than
100mV

BIG driving fource both via concentration gradient and potential gradient
What happens to Ca concentrations in nmj?
huge rise in intracellular Ca2+ only happens at active zones

normally would be dangerous, but very transient and localized
what is the change in intracellular [Ca2+] at active zone of nmj triggered by an action potential?
increases from <nM to 100-1000 microM
Lambert-Eaton syndrome
muscle weakness due to impaired release of neurotransmitter from presynaptic terminals

autoimmune disease: Abs directed against presynaptic Ca2+ channels

fewer Ca channels, less Ca entery with AP, fewer vesicles released

Rx: K+ channel blockers produce longer APs, that allow more Ca channels to be activated and restores some vesicular release
disease associated with autoantibodies against presynaptic Ca2+ channels
Lambert-Eaton, causes muscle weakness

Rx: K+ channel blockers to produce longer Action Potentials (to allow more Ca channels to be activated)
many of what are required for vesicle fusion?
proteins
toxins that block exocytosis of synaptic vesicles by proteolyzing specific proteins?
BoTOX (Botulinum)
and
Tetanus toxins inhibit chemical transmission at nmj
synaptobrevin
vesicle membrane protein

target for tetanus toxin and Botox
Syntaxin and SNAP-25
presynaptic membrane proteins

target for BoTox
BoTox targets
vesicle membrane protein: synaptobrevin
and presynaptic membrane proteins:
Syntaxin and SNAP-25
what is the nature of neurotransmitter release?
QUANTAL
(m) mean # of vesicles released per action potential = # of vesicles available for release (n) x probability of release for each vesicle (p)
what effect does low [Ca2+] around a nmj have on the probability of vesicle release?
decreases "p"

therefore decreasing "m"
what determines the quantal release of presynaptic vesicles? (m)
m = n*p

(n) THE NUMBER OF VESICLES AVAILABLE
(p) THE PROBABILITY OF RELEASE as determined by ??enviro???
describe factors contributing to quantal release at NMJ
m is usually large (~300)
large amount of transmitter
high probability of release
describe quantal nature of vesicle release in CNS
m is < 1

low quantal nature of release is very important to integration of central nervous system (don't want all-or-none release as seen in nmj)
AChE
acetylcholinesterase

terminates ACh action at the NMJ
localized to the basal lamina (ECmatrix in the synaptic cleft)
AChE regulates transmitter action by
permitting each ACh molecule to bind only once to an ACh receptor on the postsynaptic membrane, thereby limiting the time course of hte transmitter action.
why is ACh able to cross synapse (how does it survive AChE?)
far fewer molecules of AChE than ACh or AChR
where are ACh receptors (AChRs) found?
clustered at tops of postsynaptic folds
~10,000/micrometer^2 vs. 1-10micrometers^2 in the nonsynaptic membrane
High Safety Factor at NMJ reflects what?
LARGE MEAN QUANTAL CONTENT (m)
at nmj both n and p are very high
m= 300 (avg 300 vesicles of ACh released per action potential)
300 vesicles of ACh activate millions of AChRs and depolarizes postsynaptic muscle fiber well beyond threshold
Tetanus toxin and BoTox interfere with synaptic transmission by:
cleaving
Snap-35
Syntaxin
and Synaptobrevin (proteins involved in vesicular release)
Myasthenia gravis
polyclonal antibodies against ACh receptors at the nmj

decreased density of ACh receptors
simplification of junction geometry (shallow folds)
How does EPP (endplate potential) differ in a normal vs. myasthenic nmj?
normal EPP >> threshold for generating an action potential in muscle fiber (HIGH SAFETY FACTOR)

myasthenic muscle: SAFETY FACTOR IS REDUCED
even though # of quanta released is normal
# of receptors is reduced and
geometry of endplate facilitates transmitter diffusion (decreasing likelihood of transmission)
agrin
motoneuron-derived factor required for ACh receptor clustering

signals through RTK called MuSK (muscle-specific kinase)

some autoimmune myasthenia gravis involves auto-Abs against MuSK rather than AChR (these patients SEVERE deficits in neuromuscular transmission)
MuSK
Receptor Tyrosine Kinase for AGRIN (factor required for AchR clustering)

some cases of myasthenia gravis involve auto-Abs against MuSK rather than AChR
Anticholinesterases
therapeutic agents, used to treat myasthenia gravis (disease usually involving auto-Abs against AChR)

increases duration of action of ACh in synaptic cleft and probability that AChR will be activated
Muscle ACh receptor is permeable to what kind of ions?
Na+ and K+

permeability for Na+ ions is slightly > than permeability for K+ ions
What happens to Na+ and K+ ions when ACh receptor in muscle is open?
Na+ ions flow INTO the cell (Ena more positive than +40 mV)

K+ ions will flow out (Ek more negative than -80 mV)
When ACHR is open ions will flow to drive the membrane potential toward what?
the Vrev (REVERAL POTENTIAL)
that is between the Ena andthe Ek (weighted by the relative permeabilities for the two ions)

Thus the membrane potential will be driven slightly closer to Ena than to Ek (Vrev = ~0 mV)
When AChR is open there is a NET FLUX of ions in what direction?
NET FLUX of positive ions into the cell
what kind of action does ACh have at the muscle AChR?
EXCITATORY

since the Reversal Potential of 0 mV is more depolarized than Vthreshold (Vm =~-45 mV)