Excitation-Contraction Coupling in Skeletal Muscle

In a previous post, I covered excitation-contraction coupling in smooth muscle. In this post, I'll be covering excitation-contraction coupling in skeletal muscle. Unfortunately there's no nice little summary for this one, so I guess I'll have to figure out what's important :/

Excitation-Contraction Coupling

There are three main steps in the excitation-contraction coupling of skeletal muscle:

1. The action potential travels along the surface of the sarcolemma and down the transverse-tubular (T-tubular) system
2. Depolarisation activates voltage sensors (a.k.a. dihydropyridine receptors or L-type calcium channels).
3. Activation of voltage sensors opens ryanodine receptors on the sarcoplasmic reticulum (SR) membrane.

Now let's go over each step in turn!

Step 1: Action potential

The action potential works in pretty much the same way it does in most other cells: sodium influx causes the cell to depolarise and potassium efflux causes the cell to repolarise. Nothing too interesting here. The cell structures involved, however, are a bit different: the sarcolemma (muscle cell membrane) actually folds into the cell as well, creating T-tubules (transverse tubules). The action potential can travel down these T-tubules.

Step 2: Activation of voltage sensors 

As mentioned above, the voltage sensors involved are also called dihydropyridine receptors (DHP receptors, or DHPR), or L-type calcium channels. These receptors are located in the T-tubules in tetrad formations (i.e. they appear in groups of 4). They're called dihydropyridine receptors because they can be blocked by dihydropyridines, and they're called L-type calcium channels because, guess what, they let calcium through. Well, some of them do, which leads me to my next point.

Only around 5% of dihydropyridine receptors actually allow calcium through, and in fact extracellular calcium is not required for contraction, at least not in the short term. The extracellular calcium coming through these channels mainly just counteracts the calcium that is pumped out of the cell. That's not to say that they're not important: in fact, DHP receptors are critically important for contraction. It's been found that dysgenic myotubes, which have no DHP receptors, are unable to contract. How does this work, given that they're calcium channels and extracellular calcium has little effect on contraction? The answer to that question involves another function of these channels, which I'm about to introduce you to...

Step 3: Activation of ryanodine receptors (RyR)

Parts of the sarcoplasmic reticulum (SR) of skeletal muscle cells are located right next to the T-tubules. The SR has ryanodine receptors (also mentioned here and here), which are located close to the DHP receptors on the T-tubule. This allows RyRs and DHPRs to become mechanically linked, so that when DHPRs are activated, RyRs are activated too.

Let's take a closer look at the ryanodine receptor. Ryanodine receptors are made up of four monomers. They have a central channel with four side channels that branch off, and essentially release the calcium sideways (if they released calcium straight ahead, then the calcium would just bump straight into a DHPR). There are more RyRs than DHPRs- roughly every second RyR faces a DHPR.

RyRs can be stimulated by ATP and Ca²⁺. ATP is almost always bound to RyRs, unless there is a severe ATP shortage. Despite this, RyRs are usually under inhibitory control by Mg²⁺. When the DHPR is activated, certain parts (particularly the II-III loop of the α₁ subunit) interact with the RyR. This decreases the affinity of the RyR to Mg²⁺, causing release of Mg²⁺ and activation of the RyR.

When the RyR is activated, calcium can leave the SR. This calcium can then trigger contraction, as described here.

Modulation of Contraction

Contraction is not an all-or-nothing event. There are several different ways in which force can be modulated. Ca²⁺ sensitisation refers to an increased force for the same amount of Ca²⁺ (and Ca²⁺ desensitisation just has the opposite meaning). Ca²⁺ sensitisation can be modulated by temperature, pH and myosin light chain kinase. (Note: while MLCK activation was required for smooth muscle contraction, it's not required for skeletal muscle. MLCK activation simply improves the muscle's ability to contract.)

There are two main ways in which Ca²⁺ sensitisation may take place. Firstly, when the muscle is stretched, the myofilament is compressed, pushing thick and thin filaments closer together. This increases the binding probability, which in turn increases formation of crossbridges, crossbridge cycling and so on. Secondly, when MLCK is activated and able to phosphorylate the regulatory light chain, the myosin head can move closer to the actin filament, also increasing the binding probability and whatnot.

Cessation of contraction

Just like in other types of muscle, SERCA is around to pump Ca²⁺ back into the sarcoplasmic reticulum. SERCA is most highly concentrated in the longitudinal tubules, which are tubes of SR that run along the muscle fibre.

Calsequestrin, which I'm fairly sure I've spoken about before but can't find the post in which I mentioned it, is a calcium-binding protein found in the SR. Calcium binding to calsequestrin reduces the concentration of free calcium in the SR, which makes it easier for SERCA to keep pumping calcium in.

Ca²⁺-calsequestrin complexes can also associate with another protein called triadin. This Ca²⁺/calsequestrin/triadin complex can increase the opening probability of the RyR.