7.2 Lecture - G.7

• Large myelinated nerve fibers from the spinal cord's anterior horns stimulate 3 to hundreds of skeletal muscle fibers.
• Action potentials on muscle fibers travel toward the fiber ends in both directions.
• Schwann cells insulate the motor end plate from surrounding fluids.
• The space between the nerve terminal and muscle fiber membrane is the synaptic space or cleft.
• Small folds increase the surface area for synaptic transfer.

Acetylcholine Synthesis and Release

• ATP synthesizes acetylcholine in the axon terminal.
• Acetylcholine is stored in about 300,000 synaptic vesicles in the nerve terminals of a skeletal muscle fiber.
• Each vesicle contains about 10,000 acetylcholine molecules.
• Each action potential ruptures about 125 vesicles, releasing over 1.2 million acetylcholine molecules into the motor end plate.
• Acetylcholinesterase in the synaptic space destroys acetylcholine within milliseconds.

Action Potential and Calcium

• When an action potential reaches the nerve terminal, voltage-gated calcium channels open.
• Calcium ions diffuse into the nerve terminal from the synaptic space.
• Calcium allows acetylcholine vesicles to bind to the neural membrane, releasing acetylcholine into the synaptic space via exocytosis.
• Acetylcholine stimulates ion channels on the post-synaptic muscle fiber.

Acetylcholine Ion Channel

• Two acetylcholine molecules attach to alpha subunit proteins on the acetylcholine-gated sodium ion channel.
• These channels can transmit 15,000 to 30,000 sodium ions in one millisecond.
• Strong charges in the channel prevent negative ions like chloride from passing through.
• The muscle membrane's negative potential (-80 to -90 millivolts) pulls positively charged sodium ions into the muscle fiber.
• Inward sodium flow creates a local positive charge, opening neighboring voltage-gated sodium channels, leading to further sodium influx.
• The positive charge spreads along the muscle membrane, causing contraction.
• Acetylcholinesterase rapidly destroys acetylcholine.
• Acetylcholine is present in the synaptic cleft for a few milliseconds, sufficient to excite the muscle fiber.
• Acetylcholine attaches to connective tissue in the synaptic space.

Clinical Implications

• Acetylcholine inhibition is relevant in neuromuscular diseases like amyotrophic lateral sclerosis (ALS).

End Plate Potential

• Rapid sodium diffusion causes a change in charge from -80/-90 millivolts to a positive 50-75 millivolts, known as the end-plate potential.
• The action potential reaches a threshold, opening neighboring voltage-gated sodium channels. Curare poisoning and botulism toxin are conditions which do not reach the required threshold to cause an action potential.

Drugs and Diseases

• Drugs acting like acetylcholine cause localized depolarization, leading to muscle spasm.
• Drugs inhibiting acetylcholinesterase lead to acetylcholine accumulation in the neuromuscular junction.
• Diseases like myasthenia gravis reduce signaling from the nerve fiber or diminish receptors at the post-synaptic neuromuscular junction.
• These conditions can be treated with acetylcholinesterase inhibitors like neostigmine or physostigmine.

Resting Membrane Potential and Action Potential Duration

• Resting membrane potential in skeletal muscle fibers is -80 to -90 millivolts.
• Action potential duration is 1 to 5 milliseconds.
• Conduction velocity in large myelinated nerve fibers is 3 to 5 meters per second.

T Tubules

• Skeletal muscle fibers are large, action potential penetration is achieved via transverse tubules (T tubules).
• T tubules penetrate the muscle fiber from one side to the other and communicate with the exterior of the muscle fiber.
• T tubules are interior extensions of the neuromuscular junction.

Sarcoplasmic Reticulum and Calcium Release

• The sarcoplasmic reticulum contains large amounts of calcium ions.
• Voltage change in the T tubule is sensed by ryanodine receptor channels in the sarcoplasmic reticulum.
• Activation of ryanodine receptor channels opens calcium release channels.
• Muscle contraction continues as long as calcium ion concentration remains high in muscle fibers.
• A calcium pump in the sarcoplasmic reticulum walls pumps calcium back into the sarcoplasmic tubules.
• Each action potential stimulates a 500-fold increase in calcium concentration, depleted by the calcium pump.
• This calcium pulse lasts about 1/20 of a second.
• Action potentials travel down the T tubule, stimulating the ryanodine receptor channel, releasing calcium ions from the sarcoplasmic reticulum.
• Calcium pump then places the calcium back into the sarcoplasmic reticulum.

Malignant Hyperthermia

• Ryanodine receptor channel mutation can cause malignant hyperthermia, a hypermetabolic crisis.
• Triggered by certain anesthetics.
• Anesthetics cause unregulated calcium passage from the sarcoplasmic reticulum into intercellular spaces, causing excessive muscle fiber contraction.
• Leads to heat production, cellular acidosis, energy store depletion, and rhabdomyolysis.