Neuromuscular Transmission

Neuromuscular (Cholinergic) transmission is a type of synaptic transmission that occurs in the neuromuscular junction, the synapse between the axons of a motor neuron and a skeletal fiber. It relies on the binding of acetylcholine (ACh) released from presynaptic nerve terminals to acetylcholine receptors on the postsynaptic membrane. This process is very important because it enables a motor neuron to transmit a signal to the muscle fiber, causing muscle contraction.

Sequence:

1.      Action potential travels down the axon, ends in the presynaptic motor axon terminal, and opens voltage-gated calcium channels.

2.      Increase in Ca²⁺ permeability of the axon terminal causes an influx of extracellular Ca²⁺ into the axon terminal.

3.      The rise in intracellular free Ca²⁺causes the release of acetylcholine from synaptic vesicles into the synaptic cleft.

4.      Acetylcholine diffuses to the postjunctional membrane (represents a major time component).

5.      Acetylcholine binds to cholinergic receptors (ligand channels) on the postjunctional membrane, leading to the opening of the channels. The channels will remain open until the acetylcholine is removed.

6.      Opening of ligand-dependent channels results in an increased conductance to Na⁺ and K⁺. Because of the greater net force on sodium, an influx of sodium dominates.

7.      Influx of Na⁺ causes local depolarization of the postjunctional membrane. This depolarization is referred to as the end-plate potential (or EPP). The more acetylcholine that is released, the greater the depolarization (the greater the end-plate potential). Because the skeletal muscle membrane in the synaptic region does not have voltage-gated sodium channels, the action potential cannot be initiated in this region.

8.      The EPP spreads, causing depolarization of areas of muscle membrane adjacent to the end plate, where voltage-gated sodium channels are present. Their opening causes the initiation of an action potential that spreads across the surface of the skeletal muscle cell.

Single quanta of acetylcholine are released randomly under resting conditions. Each produces a small depolarization of the postsynaptic membrane, called a miniature end-plate potential (MEPP). MEPPs do not generate action potentials.

Neuromuscular transmission

Acetylcholine synthesis and choline recycling

Acetylcholine is an acetyl ester of choline. Its synthesis takes place in the cytoplasm and is catalyzed by choline acetyltransferase. Acetylcholine is then taken up into synaptic vesicles by an active vesicular transport mechanism. Acetylcholinesterase, which is weakly associated with the postsynaptic membrane and is located within the synaptic cleft, terminates the action of the transmitter via hydrolysis to acetate and choline. The active reuptake of choline from the extracellular fluid into the nerve terminal recycles the choline.

Acetylcholine synthesis and choline recycling

Reference:

Robert B. Dunn. 2002. USMLE Step 1: Physiology Notes.

Water

Water is the molecule that sustains all kinds of life forms. Its structure allows it to interact with other molecules and water molecules itself, resulting in many unique emergent properties that help make Earth suitable for life.

Polar covalent bond

Water is a polar molecule, meaning that its overall charge is unevenly distributed. In an H₂O molecule, the oxygen has two regions of partial negative charge (δ⁻) and the hydrogen has a partial positive charge (δ⁺) due to the difference in electronegativity between the two elements. Oxygen is more electronegative than hydrogen, so the electrons of the covalent bonds spend more time closer to oxygen than to hydrogen, leading to the formation of polar covalent bonds as a result in the unequal sharing of electrons.

The partial charges of water molecules make it possible for it to form hydrogen bonds with one another, through intermolecular interaction between the hydrogen of one molecule and the oxygen of another. Hydrogen bonds, as you will later see, contribute to a variety of important properties in which water possesses.

Cohesive behavior

Hydrogen bonds hold water molecules together, making it more structured than most other liquids. Several phenomena arise as a result of this behavior, such as cohesion, adhesion, and surface tension.

Cohesion: the attraction between different substances through hydrogen bonds, in this case, water molecules and other substances. Think of a straw. Without cohesion, you would not be able to suck up any water because the water molecules are unable to cling onto the surface of the straw. This is cohesion.

Adhesion: the clinging of one substance to another, in this case, water molecules to water molecules. Let’s take the straw as an example again. Without adhesion, you would again be unable to suck up any water, because the water will fall down the straw due to gravity since the molecules below are not attached to the ones above.

Surface tension: a measure of how difficult it is to stretch or break the surface of a liquid. Water has an unusually high surface tension due to its hydrogen bonding, and this can be observed in a water droplet, which has the shape of a dome.

Moderation of temperature

Water moderates air temperature by absorbing heat from the air that is warmer and releasing the stored heat to air that is cooler. Several characteristics of water allow it to do so effectively, and that is its unusually high specific heat and heat of vaporization.

Specific heat: defined as the amount of heat that must be absorbed or lost for 1 g of a substance to change its temperature by 1°C. The specific number and calculations of water’s specific heat (1 cal/g．°C) is of little importance here, and you only need to know that compared with most other substances, water has an unusually high specific heat, making it less likely to change temperature than other liquids when absorbing or losing a given amount of heat. This is due to its hydrogen bonds: a lot of heat are spend on disrupting water’s hydrogen bonds before the water molecules can begin moving faster, and when the temperature drops slightly, many additional hydrogen bonds are formed, releasing heat into its surroundings.

The heat of vaporization: the quantity of heat a liquid must absorb for 1 g of it to be converted from liquid to gas. For the same reason, that water has a high specific heat, it also has a high heat of vaporization relative to other liquids. This characteristic of water allows it to moderate Earth’s climate, through evaporative cooling and circulation of air currents across the globe.

Ice v. liquid water

Water is one of the few substances that are less dense as a solid than as a liquid. In other words, ice floats on liquid water. Water expands when solidify because its hydrogen bonds form crystalline lattices when freezing, making ice about 10% less dense than liquid water, at 4 °C. This property has many values, including the sustentation of polar ice caps and its ecosystems.

Water as a solvent

Water is a very versatile solvent, due to its characteristic of being a polar molecule. The partial charges of water molecules, both positive and negative, can surround solute ions and form a sphere of water molecules called the hydration shell. That is, a compound is identified as “water-soluble” as long as water is able to establish a hydration shell around it. This characteristic is very vital since many different kinds of polar compounds are dissolved in the water of such biological fluids like blood, the sap of plants, and the liquid within all cells.

Water as a polar molecule

Reference: 

Campbell, et al. Biology: A Global Approach. 11th ed., Pearson, 2017.

Action Potential

When a neuron responds to a stimulus, a sudden change in the voltage (stimulated by the stimulus) across the dendrites and the cell body causes specialized channels called voltage-gated ion channels to open on the surface of axons, triggering an action potential.

An action potential is defined as a rapid membrane depolarization that changes the normal resting negative potential to a positive potential follow by a repolarization back to the normal negative membrane potential.

Involved Membrane Channels

Ungated potassium channel: always open; maintains K⁺ efflux

Voltage-gated sodium channel: closed under resting conditions, quickly opens and closes when detecting nearby membrane depolarization; once closes, will not respond to a second stimulus until the cell almost completely repolarizes. This channel is required for the depolarization phase (influx of Na⁺) of an action potential, and preventing the opening of these channels, which halts depolarization, will prevent the development of an action potential.

Voltage-gated potassium channel: As is the case for the voltage-gated sodium channel, membrane depolarization is the signal that causes it to open. However, it opens more slowly than the sodium channel, and thus its opening peaks later during the action potential. It provides a rapid repolarization phase, so preventing its opening slows repolarization.

Threshold and Subthreshold

When the neuron is depolarized to a level called the threshold, it fires an action potential. Subthreshold potentials of all types are referred to as electrotonic potentials (graded potentials).

Subthreshold potential v. Action potential:

Proportional to stimulus strength (graded) │   independent of stimulus strength (all or none)

Not propagated but decremental with distance │   propagated unchanged in magnitude

Exhibits summation │   summation not possible

Depolarization phase

Initial depolarization: voltage-gated sodium channels open (opens fast, close fast). Membrane conductance to sodium increases, rapid Na⁺ influx, depolarizing the membrane close to the sodium equilibrium potential (+65 mV).

Sodium channels are opening throughout depolarization, and peak sodium conductance is not reached until just before the peak of the action potential. Even though peak sodium conductance represents a situation with a large number of open sodium channels, influx is minimal because the membrane potential is close to the sodium ion equilibrium potential (low electric force; mentioned in Resting Potential).

Repolarization phase

Early repolarization: the voltage-gated sodium channels rapidly close, eliminating Na⁺ influx. Meanwhile, the voltage-gated potassium channels are still opening (they are slower, remember?), increasing potassium conductance beyond the value under resting conditions. This leads to rapid potassium ion efflux that repolarizes the cell.

Peak potassium conductance does not occur until about mid-repolarization. At this point, even though the force on the potassium ions is less than at the beginning of repolarization, there is greater efflux because of the much greater conductance. If the voltage-gated potassium channels do not open during repolarization, the cell will still repolarize through the ungated potassium channels. However, the process will be slower.

The original gradients are reestablished via the Na/K-ATPase pump.

Refractory periods

Absolute refractory period: during this period, no matter how strong the stimulus is, a second action potential cannot be induced. Therefore, its length determines the maximum frequency of action potentials.

Relative refractory period: during this period, a greater than normal stimulus is required to induce a second action potential.

Breakdown of an action potential.

Axon Action Potential and Changes in Conductance

Reference:

Campbell, et al. Biology: A Global Approach. 11th ed., Pearson, 2017.

Robert B. Dunn. 2002. USMLE Step 1: Physiology Notes.