Montemayor DSA Flashcards
Voltage-gated sodium channel- ways of being
Closed but capable of opening (activation gate- M gate- closed; Inactivation gate- h gate- open)
Open- rapid opening triggered at threshold
Closed- with inactivation gate
May I get in? Hell no. (H gate)
potassium gates are open when?
from peak potential through
after hyperpolarization
Dependence of RMP on Extracellular K+ Concentration **
ECF [K+] affects membrane excitability
Insulin, epinephrine, aldosterone promote cellular uptake of K+
Deficiencies may result in hyperkalemia
Cell death may result in hyperkalemia
Potassium’s Contribution to the Resting Membrane Potential
↑ K+ conductance:
- ↑ K+ efflux (membrane potential becomes more negative, or hyperpolarized)
↓ ECF [K+] (Hypokalemia):
- ↑ K+ efflux
(membrane potential becomes more negative, or hyperpolarized)
↑ ECF [K+] (Hyperkalemia):
- ↓ K+ efflux (or promote K+ influx) (membrane potential becomes less negative, depolarized)
** Key: Resting membrane potential is very sensitive to changes in ECF [K+]
Synaptic transmission
Neurotransmitter molecules are synthesized and packaged in vessels
An action potential arrives at the presynaptic terminal
voltage-gated Ca2_ channels open, Ca2+ enters
A rise in Ca2+ triggerrs fusion of synaptic vesicles with the postsynaptic membrane
Transmitter molecules diffuse across the synaptic cleft and bind to specific receptors on the postsynaptic cell
Bound receptors activate the postsynaptic cell
A neurotransmitter breaks down, is taken up by the presynaptic terminal or other cells or diffuses away from the synapse
Chemical Synapse: Neurotransmitters carry signal across synapse to postsynaptic receptors
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)
Neuromuscular Junction
Specialized Synapse Between Motor Neuron & Skeletal Muscle Fiber
An axon typically synapses at a single point (NMJ or end plate), midway along the length of a skeletal muscle fiber.
NMJ Structure
- Active Zones:
Area for fusion of synaptic vesicles & release of ACh
- Clustering of synaptic vesicles
Above secondary postsynaptic clefts between adjacent postjunctional folds
- Postjunctional Folds:
Increase surface area of muscle plasma membrane
Invaginations on postsynaptic membrane opposite nerve terminal - Synaptic cleft:
~ 50 nm, time delay in impulse transmission with ACh diffusion - Nicotinic Acetylcholine Receptors:
High density expression at crests of postjunctional folds
5. Acetylcholinesterase (AChE):
High concentration
associated with synaptic
basal lamina
(basement membrane)
Terminates synaptic
transmission after AP
Nerve terminal: Site of ACh synthesis and uptake by vesicles
Choline acetyltransferase:
Synthesizes ACh from choline + acetyl coenzyme A
ACh-H+ exchanger:
ACh uptake by synaptic vesicle
Driven by vesicular proton electrochemical gradient
Synaptic Vesicle Membrane Proteins
- Synaptobrevin: (v-SNARE)
Essential for transmitter release
Forms complex with SNAP-25 & syntaxin (presynaptic membrane proteins; t-SNAREs)
Helps drive vesicle fusion
- Synaptotagmin:
Ca2+ receptor of synaptic vesicle
Detects rise in [Ca2+]i and triggers
exocytosis of docked vesicles
Vesicle Fusion
- & 4. Syntaxin & SNAP-25 (t-SNARES)
Presynaptic membrane of nerve terminal; key role in fusion process
Synaptobrevin coils around free ends of syntaxin/SNAP-25, bringing the vesicle closer to the presynaptic membrane
Exocytosis
Synaptotagmin: [Ca2+]i sensor
Ca2+ enters through voltage-gated Ca2+ channels near the active zone of the presynaptic membrane
Triggers vesicle fusion and exocytosis
Neurotoxins That Block Fusion of Synaptic Vesicles
- Tetanus toxin and botulinum toxins B, D, F, and G: endoproteinases act on synaptobrevin
- Botulinum toxins A and E: cleave SNAP-25
- Botulinum toxin C1: cleaves syntaxin
ACh Receptor
Permeable to cations (ex: Na+, K+, & Ca2+)
Current of Ca2+ is minimal and is ignored
Na+ and K+ become equally permeable
Result: increase the normally low (resting) permeability of Na+ relative to K+ →
Vm shifts to a value between EK (−80 mV) and ENa (+50 mV)
End-plate Potential = graded potential of end plate, small depolarization
Termination of Neurotransmitter Action
Acetylcholinesterase (AChE)
Enzymatic degradation removes ACh from synaptic cleft of cholinergic synapses
AChE hydrolyzes ACh to choline + acetate (2 steps)
Actin and myosin are arranged in units called sarcomeres
Sarcomere = Z line to Z line
- A band:
Myosin (thick) filaments;
Partial overlap with actin (thin) filaments - H zone:
Middle of A band;
Part of myosin where actin does not overlap - M line:
Extends vertically down center of A band - I band:
Part of actin not overlapping myosin; no project into A band - Z line:
Thin filament attachment
- Thick Filaments
Thick filament = bipolar assembly
of multiple myosin molecules:
2 myosin heavy chains (MHC)
3 regions: Rod (tail), Hinge (arm), Head
Rod: α helices
Heads:
form cross-bridges, binding
actin on thin filament
4 Light Chains
2 alkali (essential) light chains
2 regulatory light chains
2 Important Binding Sites:
Heads of heavy chains (S1 fragments) each have 2 binding sites:
1. Actin binding site (for cross-bridge formation)
- Myosin ATPase site (for binding and hydrolyzing ATP)
Thin Filaments
Actin:
F-Actin (Filamentous Actin)
Backbone of thin filament:
double-stranded α-helical
polymer of actin molecules
13 individual actin monomers form
1 helical turn on single strand of
filamentous actin (F-actin)
Associated with 2 important
regulatory, actin-binding proteins
1. Tropomyosin
2. Troponin
1 important binding site:
Myosin Binding Site
blocked by Tropomyosin at rest
Thin Filaments: Regulatory Proteins
Tropomyosin:
2 α helices coiled around each other; Regulates the binding of myosin heads to myosin binding site on actin
- Troponin:
Troponin T: binds to a single tropomyosin molecule
Troponin C: binds Ca2+
Troponin I: binds to actin and inhibits contraction
Troponin and tropomyosin
When Ca2+ combines with troponin, tropomyosin slips away from its blocking position between actin and myosin
With the exposure of the myosin-binding site on actin, a cross bridge is formed and muscle contraction can occur
Excitation-Contraction Coupling
Excitation: muscle action potential of sarcolemma –> Coupling: actin & myosin binding following ↑ [Ca2+]i –>
Contraction: power stroke/cross-bridge cycling
Triad
T-tubule membrane & 2 associated cisternae (specialized regions of the sarcoplasmic reticulum)
Crucial role in linking excitation to contraction
- Propagation of AP into T tubules depolarizes triad
- Results in Ca2+ release from lateral sacs of the sarcoplasmic reticulum
- Two important channels
1. Dihydropyridine receptor
2. Ryanodine receptor
L-type Ca2+ Channel:
Dihydropyridine (DHP) receptor
Voltage-gated channels
Role: Voltage sensor
Associated with T-tubule membrane
Tetrads: cluster in groups of 4
Conformational changes in 4 L-type
Ca2+ channels → induces a
conformational change in 4 subunits of
the Ca2+-release channel
. Ca2+- Release Channel:
Ryanodine (RyR) receptor
Role:
Releases stored Ca2+ from the SR
Associated with the SR membrane
Cluster at the portion of the SR
membrane opposite the T tubule
Summary of Events at Triad
Depolarization of voltage-sensor L-type Ca2+ channel (Dihydropyridine) on the T-tubule membrane
Mechanical activation of Ca2+-release channel (Ryanodine) in the SR
Ca2+ stored in the SR rapidly leaves through the Ca2+-release channel
Relaxation
Requires reuptake of Ca2+ from sarcoplasm back into SR
If unregulated, cross-bridge cycle would continue until myocyte is depleted of ATP
After an AP, Ca2+ must be removed from the cytoplasm for contraction to cease and for relaxation to occur
When Ca2+ levels decrease, troponin and tropomyosin move back in place and cover myosin-binding site on actin
** Relaxation = Active process!
ATP is required:
- Ca2+ pumps
- ATPase binding site on myosin head (New ATP must be bound for cross-bridge to be broken)
Pumps which Remove Calcium for Relaxation
- Na+- Ca2+ Exchanger and Ca2+ Pump
Cell can extrude Ca2+ across sarcolemma
Minor mechanisms for Ca2+
removal from the cytoplasm - Sarcoplasmic and Endoplasmic Reticulum Ca2+-ATPase (SERCA)— type Ca2+ pump
Ca2+ re-uptake into the SR
Most important mechanism for returning [Ca2+]i to resting levels in skeletal m.
Ca2+- Binding Proteins in the SR
High [Ca2+] in the SR inhibits activity of SERCA (impacts gradient)
Ca2+-binding proteins in the SR lumen can delay inhibition of Ca2+ pump activity
Calsequestrin: Major Ca2+-binding protein in skeletal muscle
Localized in SR at triad junction
Forms complex with Ca2+-release channel (RYR)
Facilitates muscle relaxation by buffering Ca2+ AND unbinds Ca2+ near Ca2+-release channel
