Neuro L4 Synapses

Front 1

Gap junction channel is built from...

Back 1

six identical subunits called CONNEXINS

Front 2

Gap junction channels allow movement of what?

Back 2

allows current to flow directly from one cell to the next

allows passage of small molecules (cAMP, Ca2+ that have signalling capabilities)

Front 3

When/where are GAP JUNCTIONS most commonly found?

Back 3

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)

Front 4

What regulates expression of the CONNEXINS that make up gap junctions

Back 4

e.g. by steroid hormones

Front 5

Permeability of GAP JUNCTIONS is regulated by:

Back 5

second messengers
pH
and Ca2+

Front 6

mutations in the genes encoding different connexins are believed to underlie what diseases?

Back 6

1. CONGENITAL RECESSIVE NONSYNDROMIC DEAFNESS
and PROGRESSIVE DOMINANT DEAFNESS

2. CHARCOT MARIE TOOTH (CMT disease)

Front 7

Connexin mutations can cause deafness because

Back 7

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

Front 8

mutations in what gene may account for 10% of all congenital hearing loss

Back 8

connexin 26

Front 9

Charcot Marie Tooth (CMT) disease

Back 9

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

Front 10

loss of gap junctions between overlaying loops of Schwann cells underlies what disease?

Back 10

Charcot Marie Tooth disease

characterized by diminished conduction of both: MOTOR and SENSORY axons

Front 11

Fundamental properties of chemical synaptic transmission

Back 11

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

Front 12

what is required for exocytosis of presynpatic vesicles?

Back 12

influx of Ca2+ ions upon depolarization

Front 13

how long does it take for an action potential to travel from a presynaptic nerve terminal through the post-synaptic receptor?

Back 13

~500 microseconds

due to fast release of neurotransmitter and opening of postsynaptic receptors

Front 14

specificity of chemical transmission is conferred by

Back 14

specific cognate receptors for each neurotransmitter in postsynaptic membrane

Front 15

bulk of communication in the nervous system is...

Back 15

chemical in nature

Front 16

Sequence of events in neurotransmitter release

Back 16

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

Front 17

2 major classes of neurotransmitters

Back 17

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

Front 18

2 major classes of neurotransmitter receptors

Back 18

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)

Front 19

IONOTROPIC RECEPTORS
type of receptor:
time range:

Back 19

ligand-gated ion channels

time range: msec

Front 20

METABOTROPIC NEUROTRANSMITTER RECEPTORS
time range:

Back 20

G protein-coupled
and activation of 2nd messenger signalling pathways

time scale: msec to minutes or longer

Front 21

Examples of small molecule neurotransmitters

Back 21

biogenic amines (dopamine, norepi, epi, 5-HT, histamine)
glutamate
GABA
glycine
ACh
Purines

Front 22

Examples of larger neuropeptide and neurohormone neurotransmitters

Back 22

over 50 id'd

opioids
cannabinoids
substance P

Front 23

major inhibitory neurotransmitter in the brain

Back 23

GABA (smalle molecule neurotransmitter)

Front 24

what determines whether chemical transmission is inhibitory or excitatory?

Back 24

determined by neurotransmitter receptors (which are inhibitory or excitatory)

neurotransmitters are NOT

Front 25

Depolarization

Back 25

lessening of membrane potential (eg. from -70 to -40 mV)

Front 26

Hyperpolarization

Back 26

increasing of membrane potential (e.g., from -60 to -90 mV)

Front 27

EPSP/EPSC

Back 27

excitatory postsynaptic potential/current

Front 28

IPSP/IPSC

Back 28

inhibitory postsynaptic potential/current

Front 29

EPP

Back 29

specialized neuromuscular excitatory synaptic potential END PLATE POTENTIAL

Front 30

Excitation:

Back 30

change in Vm that makes it more likely that Vm will exceed the threshold for generating an action potential (depolarization)

Front 31

Inhibitions

Back 31

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)

Front 32

nicotinic acetylcholine receptors
(skeletal muscle and neuronal) are:
what type of receptors?
relay what type of signal?

Back 32

Ionotropic Receptors

EXCITATORY

Front 33

glutamate receptors (NMDA and AMPA)

receptor type?
signal type?

Back 33

Ionotropic Receptor

EXCITATORY
(?mediate fast inhibition)

Front 34

Purinergic receptors (bind adenosine or ATP)
receptor type?
signal type?

Back 34

Ionotropic Receptor

EXCITATORY

Front 35

GABAa receptors
found where?
receptor type?
signal type?

Back 35

found mainly in brain
IONOTROPIC receptors
Inhibitory
**excitatory in dvpg brain and adult neurons after injury

Front 36

Glycine receptors
found where?
receptor type?
signal type?

Back 36

mainly expressed in spinal cord
IONOTROPIC receptors
Inhibitory
**excitatory in dvpg brain and adult neurons after injury

Front 37

5-HT3 class of serotonin receptors
receptor type?
signal type?

Back 37

IONOTROPIC
Excitatory

Front 38

examples of compounds that can activate both ionotropic and metabotropic receptors

Back 38

GABA
glutamate
serotonin
ATP
ACh

Front 39

muscarinic ACh receptor is what kind of receptor?

Back 39

metabotropic receptor

Front 40

nicotinic ACh receptor is what kind of receptor

Back 40

ionotropic (excitatory) receptor
(Neuronal and skeletal muscle0

Front 41

GABAb receptor is what kind of receptor?

Back 41

metabotropic

Front 42

what kind of receptors are GABAa and GABAc?

Back 42

ionotropic
inhibitory

Front 43

Glutamate receptors that are
a) ioniotropic
b) metabotropic

Back 43

a) NMDA
AMPA
Kainate
b) ACPD

Front 44

which class of 5-HT receptor is ionotropic?

Back 44

5-HT 3

Front 45

neurons in the CNS receive about how many synapses?

Back 45

tens of thousands

purkinje cell dendrites covered with presynpatic terminals (eg from granule cells)

Front 46

neuromuscular junction involves what type of fibers?

Back 46

involves fast twich fibers

Front 47

each postsynaptic muscle fiber is innervated by...

Back 47

a single motor neuron axon at a single well-define postsynaptic site

Front 48

how efficacious is synaptic transmission at NMJs?

Back 48

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

Front 49

Multiple muscle fibers can receive synaptic input from the same

Back 49

neuron

Front 50

Active Zones of NMJ

Back 50

site of neurotransmitter release in presynaptic membrane of NMJ

Front 51

where are vesicles found in NMJs

Back 51

docked at active zones via:
-protein complexes between vesicle and plasma membranes and..
-association with cytoskeleton in the presynaptic terminal

Front 52

vesicles at nmp contain what as the primary neurotransmitter?

Back 52

ACh

Front 53

What is required for exocytosis triggered by action potentials

Back 53

Ca influx (via Voltage dependent Ca channels)

opened by depolarization from invading action potential

allows vesicles to fuse to membrane and exocytose neurotransmitter

Front 54

Where are Ca channels found in nmj

Back 54

localized to active zones

Front 55

At nmj

Eca is greater than

Back 55

100mV

BIG driving fource both via concentration gradient and potential gradient

Front 56

What happens to Ca concentrations in nmj?

Back 56

huge rise in intracellular Ca2+ only happens at active zones

normally would be dangerous, but very transient and localized

Front 57

what is the change in intracellular [Ca2+] at active zone of nmj triggered by an action potential?

Back 57

increases from <nM to 100-1000 microM

Front 58

Lambert-Eaton syndrome

Back 58

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

Front 59

disease associated with autoantibodies against presynaptic Ca2+ channels

Back 59

Lambert-Eaton, causes muscle weakness

Rx: K+ channel blockers to produce longer Action Potentials (to allow more Ca channels to be activated)

Front 60

many of what are required for vesicle fusion?

Back 60

proteins

Front 61

toxins that block exocytosis of synaptic vesicles by proteolyzing specific proteins?

Back 61

BoTOX (Botulinum)
and
Tetanus toxins inhibit chemical transmission at nmj

Front 62

synaptobrevin

Back 62

vesicle membrane protein

target for tetanus toxin and Botox

Front 63

Syntaxin and SNAP-25

Back 63

presynaptic membrane proteins

target for BoTox

Front 64

BoTox targets

Back 64

vesicle membrane protein: synaptobrevin
and presynaptic membrane proteins:
Syntaxin and SNAP-25

Front 65

what is the nature of neurotransmitter release?

Back 65

QUANTAL
(m) mean # of vesicles released per action potential = # of vesicles available for release (n) x probability of release for each vesicle (p)

Front 66

what effect does low [Ca2+] around a nmj have on the probability of vesicle release?

Back 66

decreases "p"

therefore decreasing "m"

Front 67

what determines the quantal release of presynaptic vesicles? (m)

Back 67

m = n*p

(n) THE NUMBER OF VESICLES AVAILABLE
(p) THE PROBABILITY OF RELEASE as determined by ??enviro???

Front 68

describe factors contributing to quantal release at NMJ

Back 68

m is usually large (~300)
large amount of transmitter
high probability of release

Front 69

describe quantal nature of vesicle release in CNS

Back 69

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)

Front 70

AChE

Back 70

acetylcholinesterase

terminates ACh action at the NMJ
localized to the basal lamina (ECmatrix in the synaptic cleft)

Front 71

AChE regulates transmitter action by

Back 71

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.

Front 72

why is ACh able to cross synapse (how does it survive AChE?)

Back 72

far fewer molecules of AChE than ACh or AChR

Front 73

where are ACh receptors (AChRs) found?

Back 73

clustered at tops of postsynaptic folds
~10,000/micrometer^2 vs. 1-10micrometers^2 in the nonsynaptic membrane

Front 74

High Safety Factor at NMJ reflects what?

Back 74

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

Front 75

Tetanus toxin and BoTox interfere with synaptic transmission by:

Back 75

cleaving
Snap-35
Syntaxin
and Synaptobrevin (proteins involved in vesicular release)

Front 76

Myasthenia gravis

Back 76

polyclonal antibodies against ACh receptors at the nmj

decreased density of ACh receptors
simplification of junction geometry (shallow folds)

Front 77

How does EPP (endplate potential) differ in a normal vs. myasthenic nmj?

Back 77

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)

Front 78

agrin

Back 78

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)

Front 79

MuSK

Back 79

Receptor Tyrosine Kinase for AGRIN (factor required for AchR clustering)

some cases of myasthenia gravis involve auto-Abs against MuSK rather than AChR

Front 80

Anticholinesterases

Back 80

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

Front 81

Muscle ACh receptor is permeable to what kind of ions?

Back 81

Na+ and K+

permeability for Na+ ions is slightly > than permeability for K+ ions

Front 82

What happens to Na+ and K+ ions when ACh receptor in muscle is open?

Back 82

Na+ ions flow INTO the cell (Ena more positive than +40 mV)

K+ ions will flow out (Ek more negative than -80 mV)

Front 83

When ACHR is open ions will flow to drive the membrane potential toward what?

Back 83

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)

Front 84

When AChR is open there is a NET FLUX of ions in what direction?

Back 84

NET FLUX of positive ions into the cell

Front 85

what kind of action does ACh have at the muscle AChR?

Back 85

EXCITATORY

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