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39 Cards in this Set

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Scheme of AP action
AP-->depolarizes nerve terminal-->open voltage gated calcium channels-->local calcium levels rise in nerve terminal-->transmitter release
Synaptic Delay
time between presynaptic AP and postsynaptic effect,about 1 msec, hal of which is until calcium channels open
Normal concentration of Ca
normal extracellular calcium=2 mM
resting intracellular calcium = 10-100 nM
5 orders of magnitude difference, bigger difference than Na or K
What allows for Ca to be a signaling ion?
low intracellular calcium concentration
Experiments done by Katz
Katz hypothesized that calcium entered nerve terminal and regulated vesicular release
1) remove calcium from bath --> no release, although AP activity and postsynaptic sensitivity same
2)Katz calcium pulse experiment
3)Add ionic blocker (Mg or Cd) block release (blocks calcium flux by competeition)
Concluded calcium is necessary for release
New experiments to show calcium is sufficient to trigger release
calcium ionophore causes release
load terminal with caged calcium, liberation induces transmitter release
calcium liposomes
Why doesnt injected free calcium work?
rapid buffering
Two major transport systems
1. Ca-Mg-ATPase - activated by intracellular calcium, high affinity for calcium(> 300 nM), Mg is needed as a co factor for ATP building, one calcium moved out of the cell for every ATP hydrolyzed
2. Na-Ca exchanger--> activated by intracellular calcium, lower affinity for Ca, driven by electrochemical gradient for Na, one calcium extruded for three Na ions entering cell, doesnt have rapid or potent effect on membrane potential
Buffers of Ca
Endoplasmic reticulum, mitochondria, proteins. Buffering - regulatory point
EGTA
high affinity, low speed of binding --> no effect on release
BAPTA
high affinity, fast speed --> blocks release. Need faster buffer to grab calcium after it enters the nerve terminal and before it binds to secretory apparatus, so calcium entry and release apparatus must be very close to one another
What concentration of calcium do we need to get transmitter release
10- 100 micro molar
Microdomains
microdomains are hypothesized to be calcium just under calcium channel that triggers transmitter release
Paired pulse facilitation
when two stimuli are delivered in rapid succession, second stimuli evokes larger response the first
Tetanic potentiation
during a train of multiple stimuli at high frequency, there is a gradual increase in the amount of transmitter released
Post tetanic potentiaiton
after a train of stimuli has ended, there is an increase in the amount of transmitter release with single stimuli at low frequency for some time
Model systems that allow to patch a nerve terminal
squid giant synapse, chick calyx, auditory calyx of Held, Xenopus nerve muscle cultures
Ca I-V relationship
similar to Na due to similar DF and activation curves
Tail current
deactivation at micro and macro current scale, not seen much with Na channels because they inactivate too fast
What is the relationship between calcium and NT release
Release is very sensitive to Ca--> drop Ca-drop release
what is the equation to describe relationship between Ca and release
fold change in postsynaptic measure of release = fold change in calcium concentration raised to 3-4
On a log log plot straight line with slope of 3-4
ex ca change 0.15=0.3 2 fold change, postsynaptic change 0.25 - 4 (16 fold ) 2^4 = 16
What does this relationship mean
It is important for modulation of synapses, a small change in calcium current can have a big effect on the release, easier for plasticity to occur
Name types of Ca channels that have been shown to regulate transmitter release
mammalian NMJ = P type
amphibian/chick NMJ = N type
What is the role of Ca activated K channels
Kca channels can shape action potential even with single APs and thus indirectly change transmitter release by changing voltage pulse (AP) that triggers Ca entry. Need to be close to Ca channels and respond very quickly.
What happens when you block voltage gated K channels
broaden AP from peak and increase peak calcium and release
What happens when you block Ca activated K channels
broaden AP from half way down and decrease peak calcium and release
Describe LEMS
LAMBERT EATON MYASTHENIC SYNDROME
autoimmune disease in which body attacks its own Ca channels at active zones of NMJ, clinically related to small lung cancer, tumor cells are like neuroendocrine cells and recognized as foreign by immune system, body makes antibodies to calcium channels on these cells (P/Q type). Antibodies reduce number of Ca channels in nerve terminal by crosslinking them and removing them from plasma membrane, patient feels weak because not all of nerve terminals release enough Ach to cause muscle AP.
What is the treatment of LEMS
block K channels, prolong AP to increase Ca entry, increase release
Synapsin 1
keeps vesicles in the meshwork of actin, has a head domain that binds to phospholipids in the vesicle membrane and inserts into hydrophobic regioon. Tail associates with a specific vesicle membrane protein, also has two high affinity binding sites for actin in head region. Regulated by phosphorylation
What phosphorylates synapsin
cAMP- PK and specific CaM kinase I and CaM kinase II
Phosphorylation at site 1 diminishes binding to actin, at sites 2 and 3 reduces affinity of synapsin 1 to vesicles and abolishes binding to acti
Unoccupied vesicle docking area
syntaxin (associated with nsec 1) binds calcium channel. At rest syntaxin is bound by nsec 1 and VAMP is bound by other vesicle proteins. This normally inhibits docking of vesicles
Targeting of vesicles to active zone area
Exocyst (complex of proteins) interacts with cytoskeleton to transport vesicles to active zone area after they released by synapsin, acts as chaperon for vesicle to find active zone.
Tethering of vesicles to docking area
Rab 3 (GTPase) may regulate the alignment of vesicles in the docking area and may assist in the displacement of nsec 1 from syntaxin.
Docking
Syntaxin and SNAP 25 bind to VAMP to form CORE complex
T Snare
terminal membrane receptors for these cytoplasmic proteins
V Snare
vesicle membrane receptors for cytoplasmic proteins
Priming
CORE complex binds synaptotagmin and forms 4 protein docked complex - VAMP and synaptotagmin on the vesilce bind to syntaxin and SNAP 25 on plasma membrane, 7S complex - stable on denaturing gels
Fusion
Synaptotagmin hold this configuration as a clamp waiting for calcium entry
Recycling/Recovery
Cytoplasmic NSF/alpha SNAP break up CORE complex so that it can be recycled by joining association with VAMP, SNAP 25 and syntaxin, hydrolyzing ATP and kicking out synaptotagmin, 20 S complex - stable on denaturing gels