skeletal muscle an the neuromuscular junction Flashcards
characteristics of skeletal muscle
- striated
- voluntary: somatic innervation
- multinucleated
- contain satellite cells for repair
name skeletal muscle organization from muscle fibers to myofilaments
- muscles are composed of muscle fibers
- muscle fibers are composed of bundles of myofibrils
- myofibrils consist of a bundle of parallel microfilaments called myofilaments
- myofilaments are organized into contractile units called sarcomeres
what is the smallest functional unit of skeletal muscle
sarcomere
what are the two types of myofilaments
- myosin
- actin
How many neurons innervate one fiber at one location?
- each fiber innervated by ONE neuron at one location
what makes up a motor unit
one neuron can innervate many fibers (motor unit)
why do muscle fibers (cells) contain satellite cells
responsible for repair of muscle
what is excitation-contraction coupling
electrical stimulus (action potential) converted to mechanical response (contraction)
synaptic vesicles contain what neurotransmitter
acetylcholine (Ach)
active zone of neuromuscular junction
storage and release site for vesicles
motor endplate of neuromuscular junction
sarcolemma opposite to synaptic terminals; has receptors for Ach
What are Ach receptors at neuromuscular junction
- mixed-cation channel (simultaneous Na+ and K+)
End Plate Potential (EPP) at neuromuscular junction
- depolarizing graded potential that results from the opening of Ach receptors
- EPP reaches threshold and initiates action potentials
characteristics of Motor end plate
- portion of sarcolemma directly across from the synaptic terminal
- Ion channels in motor end plate are chemically-gated (bind acetylcholine)
- capable of End plate potential (EPP), NOT action potentials
characteristics of sarcolemma
- plasma membrane of a muscle fiber
- electrically similar to axonal plasma membranes
- can propagate self-regenerating action potentials
- action potentials due to voltage gated Na+ channels
What type of potential is localized to motor end plate
graded potential EPP
what causes 1 miniature end-plate potential (MEPP)
each vesicle release of Ach
1 vesicle contains how many Ach molecules?
1 quantum = 10,000 Ach molecules
Summation of multiple MEPPS (miniature end-plate potentials) produce what?
an EPP
what does the EPP magnitude depend on?
depends on the amount and duration of Ach at the end plate
List the steps of neuromuscular transmission from beginning (traveling AP) to diffusion of neurotransmitter to sarcolemma
- Action potential arrives in presynaptic motorneuron axon terminal
- opening of voltage-gated CALCIUM channels and entry of calcium into axon terminal
- release of Ach from synaptic vesicles into synaptic cleft
- diffusion of Ach to sarcolemma
what happens when Ach binds to Ach receptors on the motor end plate within sarcolemma
- the conductance of the motor end plate to Na+ and K+ (predominantly Na+) increases
- results in EPP
how is a action potential on sarcolemma initiated
depolarization of muscle membrane adjacent to motor end plate reaches threshold and opens voltage-gated channels which initiate AP on sarcolemma
action of acetylcholinesterase (AChE)
degradation of acetylcholine
how do synaptic vesicles get to the synaptic membrane
SNARE proteins
what are the SNARE proteins
- synaptobrevin
- SNAP-25
- Syntaxin
binding of Ach to the receptor on the motor end plate allows for the channel to open to what?
- Na + (goes in)
- K+ (goes out)
factors that can affect the magnitude of EPP
- voltage-gated calcium channel function
- amount of Ach release
- rate of Ach breakdown
- Ach receptor agonists and antagonist
what is the margin of safety
difference between the size of the EPP and the size of the threshold stimulus necessary to evoke an AP
normally, how many single motor neuron action potentials can cause a large enough EPP to initiate a muscle cell AP
a single motor neuron AP
why is there a margin of safety
- there is typically far more Ach (3x) released and receptors activated than needed for depolarization
- ensures that muscles activate every time signal is sent
- prevents catastrophic failure of neuromuscular transmission and provides a buffer to ensure every time
where is acetylcholinesterase located
- located in junctional gap and post-synaptic folds
- rapidly degrades Ach
Acetylcholinesterase breaks acetylcholine into what two molecules? What happens to them?
- Acetate and choline
- choline is returned to the synaptic knob where it is recycled and reformed with acetyl Co-A into Acetylcholine
How does acetylcholine, synthesized in the synaptic knob (from acetyl Co-A and choline) get transported into the vesicles
- via a second messenger ACh-H exchanger (ACh comes in and H+ leaves vesicle)
- a ATP generated proton pump provides the H+ into the vesicle necessary for the ACh-H exchanger
What is the Botulism toxin’s effect on SNARE proteins. How can this be harmful? How can this be beneficial?
- causes degradation of SNARE proteins
- prevents fusion of synaptic vesicles
- causes: flaccid paralysis and death via respiratory paralysis
- Used clinically to treat many conditions including muscle spasms
What the mechanism of action of the drug Curare
- competitive antagonist: competitively blocks binding of Ach to receptors
- causes: paralysis
- reversible
- used during surgery as a adjunct to but not as a replacement for anesthesia
What is the mechanism of action in the disease Myasthenia Gravis
- circulating antibodies block Ach receptors and cause them to be endocytosed and degraded
- EPP decreases
- decreased margin of safety
- recruitment declines with use; some motor units fail to reach threshold due to decreased margin of safety
Why is Neostigmine used to treat Myasthenia Gravis
- it is a reversible acetylcholinesterase inhibitor
- prolongs and enhances action of ACh at motor end plate
What is the mechanism of action of Hemicholinium
- blocks reuptake of choline into presynaptic terminal
- depletes ACh stores from presynaptic terminal
The action potential travels through the entire sarcolemma and into what structure?
Transverse T-tubules
where is calcium stored in the muscle
sarcoplasmic reticulum
what is a triad?
proximity of the two sarcoplasmic reticulum membranes and a T-tubule
T-tubles contain what type of calcium channels
slow-activating voltage-gated Ca2+ channels called DHP receptors in skeletal muscle
The sarcoplasmic reticulum membrane contains what type of Ca2+ channels
Ca2+ release channels callled Ryanodine receptors (RYR)
how is calcium released from the Sarcoplasmic reticulum
- upon depolarization of the T-tubles, a conformational change occurs in the DHP receptor that mechanically opens the RYR on the SR
- calcium is then releases from the SR
function of calsequestrin (Casq)
- calcium binding protein in the SR
- allows the SR to store a large amt of calcium
- keep free calcium concentration in SR low
Malignant Hyperthermia
- inherited syndrome: sensitive to anesthetics
- gene mutation in RyR and calsequestrin or DHD receptor
- Ca2+ channel of SR is abnormally sensitive to anesthetic
- release of Ca2+ is uncoupled from sarcolemmal AP
- skeletal muscles contract forcefully w/o AP
treatment for malignant hyperthermia
dantrolene sodium
- muscle relaxant that abolishes E-C coupling by acting on the RyR
myosin and actin, which is thick and which in thin filament
myosin (thick)
actin (thin)
composition of myosin filament
- each myosin molecule is composed of two proteins twisted together forming a tail with two heads (Cross-bridge)
- myosin has ATPase activity
composition of actin filament
core of a single actin filament consists of many actin globular molecules (G-actin) as a two stranded helical structure
role of Tropomyosin
inhibits binding of myosin to actin
role of Troponin (Tn) (3 parts)
Ca2+ -sensitive molecular switch
- TnC: calcium binding produces conformational change in Tnl
- TnT: links Tn complex to tropomyosin
- Tnl: binds to actin and inhibits myosine ATPase
role of calcium in the regulation of myosin binding to actin
- Ca2+ binding to troponin complex allows for physical repositioning of tropomyosin filament, which exposes the myosin binding site on the actin molecules
sliding filament theory
- contraction occurs by the sliding of thin filaments past thick filaments: sarcomere shortens
- result: muscle shortening
- contractile force produced by muscle iber is proportional to the number of myosin cross-bridge-actin interactions
cross-bridge cycling: energized state
- cytosolic Ca2+ low
- myosin and actin: dissociated
- myosin head holds ADP and Pi
- binding site on actin is blocked by tm/tn complex
list step that lead to myosin binding to actin from the AP
- AP causes release of Ca2+ from SR
- Ca2+ binds to Troponin C
- conformation shift in Tm/Tn complex
- exposure of myosin binding to actin
- myosin binds to actin
- Pi release initiates the “powerstroke”
what goes on during the Powerstroke
- myosin head shift causing filament to slide
- ADP released
- myosin remains bound to acting until new ATP binds
how does myosin become re-energized
- ATP binds to myosin causes it to release actin
- ATP hydolyzed to ADP - Pi
- energy released is stored in conformational shift of myosin head back to energeized state
- next cross-bridge cycle can occur
How is calcium removed from the ICF back into the sarcoplasmic reticulum
via sarcoplasmic reticulum Ca2+ ATPase (SERCA)
- triggered by high concentrations of Ca2+
- must occur quickly
