At what voltage are the M gates closed on the voltage sodium channels?
What voltage range is the threshold to peak potential that causes voltage gated Na+ channels to open?
-50 mV to +30 mV
At what voltage range are the H gates of Na+ channels closed?
Are they capable of opening at this point?
+30 mV to -70 mV
No, when h gates (inactivation gates) are closed, they cannot open again (unlike M gates - activation gates)
Voltage gated K+ channels are closed but capable of opening at RMP, and remain closed to peak potential. What range is this occuring at?
-70 mV to +30 mV
When are voltage gated potassium channels open?
- Open from peak potential through after hyperpolarization
- (+30 mV to –80 mV)
ECF [K+] affects membrane excitability, what are three hormones that promote cellular uptake of K+?
What happens to membrane potential in hypokalemia?
–↑ K+ efflux leads to membrane potential becomes more negative, or hyperpolarized
What does hyperkalemia do to membrane potential?
–↓ K+ efflux (or promote K+ influx) (membrane potential becomes less negative, depolarized)
** Key: Resting membrane potential is very sensitive to changes in?
Fill in the blanks!
What are the six steps of NT signaling across the synapse?
- AP at axon terminal of presynaptic neuron opens voltage-gated Ca2+ channels
- Ca2+ influx from ECF into synaptic knob
- Ca2+ influx induces fusion & exocytosis of synaptic vesicles → neurotransmitter into the synaptic cleft
- N.T.s diffuse & bind to receptors on subsynaptic membrane of the postsynaptic neuron
- Bound N.T.s result in alteration of membrane permeability of postsynaptic neuron
- Termination of signal by removal of N.T. from synaptic cleft (enzymatic breakdown, cellular uptake, diffusion)
What are the 5 components of the NMJ?
- Active zones
- Postjunctional Zones
- Synaptic cleft
- Nicotinic Ach receptors
What happens at the active zones of the NMJ?
Where are they?
• Area for fusion of synaptic vesicles & release of ACh, with Clustering of synaptic vesicle.
• Above secondary postsynaptic clefts between adjacent postjunctional folds
What are the postjunctional folds and where are they located?
What is their purpose?
• Invaginations on postsynaptic membrane opposite nerve terminal
•Increase surface area of muscle plasma membrane
There is a time delay in impulse transmission because the NTs have to diffuse across the cleft. How wide is the cleft?
Where are nicotinic ACh receptors expressed in high concentration?
•crests of postjunctional folds
AChE terminates the synptic transmission after the AP by hydrolizing ACh to choline and acetate. Where are these enzymes expressed in high concentration?
• High concentration associated with synaptic basal lamina (basement membrane)
what is the enzyme that synthesizes ACh from choline and acetyl coenzyme A?
The ACh-H+ exchanger is responsible for uptake by synaptic vesicle. What is this process driven by?
By vesicular proton electrochemical gradient - ACh influx coupled with H+ efflux (due to positive voltage and low pH inside)
What is the vesicle membrane protein responsible for transmitter release?
What does synaptobrevin form a complex with?
SNAP-25 and Syntaxin
What are the functions of synaptobrevin?
NT release via vesicle fusion
What is the Ca++ receptor of synaptic vesicles?
What does synaptogamin do?
• Detects rise in [Ca2+]i and triggers exocytosis of docked vesicles
What are the synaptic vesicle proteins responsible for fusion of the NT vesicles with the presynaptic membrane?
Syntaxin and SNAP-25 (t-snares)
Syntaxin & SNAP-25 (t-SNARES) are integrated into the presynaptic membrane of nerve terminal and play a key role in fusion process. How do these interact with the vesicles?
•Synaptobrevin coils around free ends of syntaxin/SNAP-25, bringing the vesicle closer to the presynaptic membrane
What is the target of tetanus toxin?
What botulinum toxins target synaptobrevin?
B, D, F, G
What botulinum toxins target SNAP-25?
What does botulinum toxin C1 target?
Tetanus toxin and botulinum toxins B, D, F, and G are ___________ that act on synaptobrevin.
Describe what is happening at each point shown in this representation of the NMJ.
- AP is propagated to terminal boutton.
- AP in terminal boutton opens V-gated Calcium channels and Ca++ flows into the terminal boutton.
- Ca++ triggers release of ACh through vesicle exocytosis
- ACh diffuses across and binds to receptors on motor end plate
- This opens cation channels leading to large influx of Na+ and small K+ efflux
- This cation flow produces an end plate potential - local current flow occurs between the depolarized end plate and adjacent membrane
- Local current opens V-gate Na+ channels in the adjacent membrane
- Na+ entry reduces the potential to threshold and propagates and action potential through the muscle fiber
- ACh is subsequently destroyed by AChE, terminating the muscle cell response
A sarcomere is defined by what borders?
Sarcomere = Z line to Z line
What are the components of the sarcomere?
- A Band
- H Zone
- M line
- I band
- Z line
What is the A band?
Myosin (thick) filaments; Partial overlap with actin (thin) filaments
Where is the H zone? What is noteable about this area?
- Middle of A band;
- Part of myosin where actin does not overlap
Where is the M line found?
Extends vertically down center of A band
Describe the I band
Part of actin not overlapping myosin; no projection into A band
What is the Z line?
Thin filament attachment point
What are thick filaments comprised of?
2 myosin heavy chains
4 light chains
What are the 3 regions of the myosin heavy chains (MHC)?
Rod (tail), Hinge (arm), Head
What is the shape of the MHC rod?
What do the MHC heads do?
form cross-bridges, binding actin on thin filament
What are the four light chains involved in the thick filament?
•2 alkali (essential) light chains
• 2 regulatory light chains
The MHC heads (S1 fragments) have two binding sites. What are they and what do they do?
1. Actin binding site (for cross-bridge formation)
2. Myosin ATPase site (for binding and hydrolyzing ATP)
Thin filaments are made of what?
What are the two important regulatory actin binding proteins?
What does tropomyosin do?
Blocks the myosin binding site at rest
What are the three troponins we covered?
What does troponin T bind?
Troponin T: binds to a single tropomyosin molecule
Troponin C: binds Ca2+
Troponin I: binds to actin and inhibits contraction
What happens when Ca++ combines with troponin?
Tropomyosin slips away from its blocking position between actin and myosin
When the myosin binding site is exposed on actin, what happens?
A cross bridge is formed and muscle contraction can occur
What are the components of the sarcoplasmic reticulum triad?
•T-tubule membrane & 2 associated cisternae (specialized regions of the sarcoplasmic reticulum)
The sarcoplasmic reticulum Triad has a crucial role in linking the excitation to contraction. How does it do this?
–Propagation of AP into T tubules depolarizes triad
–Results in Ca2+ release from lateral sacs of the sarcoplasmic reticulum
What are the two important channels of the Triad?
1. Dihydropyridine receptor
2. Ryanodine receptor
What type of channel is the Dihydropyridine (DHP) receptor?
L-type Ca2+ Channel
What membrane is the DHP receptor associated with?
DHP receptors are clustered in tetrads. What do the conformational changes in these 4 L-type channels induce?
induces a conformational change in 4 subunits of the Ca2+-release channel
What dos the RyR receptor do?
Releases stored Ca2+ from the SR
What membrane is the RyR receptor associated with?
Muscle relaxation is what kind of process?
Active - ATP is required
What role does ATP play in relaxation of muscle fibers?
•Ca2+ pumps ATPase binding site on myosin head
(New ATP must be bound for cross-bridge to be broken)
Calcium must be removed from the cell to permit relaxation of the muscle. How is this accomplished?
- Na+- Ca2+ Exchanger
- Ca2+ Pump
- Na+- Ca2+ Exchanger and Ca2+ Pump
What is the major mechanism for calcium removal from the muscle cell?
SERCA pump - by far the most important mechanism
Where does the SERCA pump ship calcium to?
•Ca2+ re-uptake into the SR
In what situations is the SERCA pump inhibited?
High Ca++ in the SR inhibits SERCA activity
Calsequestrin is the major Ca++ binding protein in skeletal muscle and is located at the triad junction of the SR. What does it complex with?
What does calsequestrin do?
–Facilitates muscle relaxation by buffering Ca2+ AND unbinds Ca2+ near Ca2+-release channel
What does calreticulin do?
It is a Ca++ binding protein in smooth muscle (this is all the DSA says about it, so I guess not so important)