Smooth Muscle Response to Stretch

Last post on smooth muscle!

Explain how myogenic tone develops in vascular smooth muscle

As mentioned here, some smooth muscles, including those of the vascular system, contract in response to stretch. This process requires calcium to enter the cell from outside, and is thus blocked by nifedipine (a blocker of L-type calcium channels). But how exactly does this process work? Read on...

Describe the possible pathways for myogenic tone including the role of TRPC3,6, TRPM6, L-type channels, GPCR and autocrines.

Stretch-Gated Channels (SGCs)

There are many non-selective, stretch-activated channels in vascular smooth muscle. These are called stretch gated channels, or SGCs. The main ones include the epithelial sodium channel (ENaC), TRPC3, TRPC6 and TRPM4. Now, that's a lot of letters, so lets break it down. The TRP refers to the Transient Receptor Potential (TRP) family, the C or M refers to the family, and the number refers to the specific member of the family.

As there are a lot of different channels that might be involved, they can compensate for one another. Mice that lack the genes for TRPC6 appear to have upregulated TRPC3. This is probably why these mice still have the myogenic response.

G-Protein Coupled Receptors (GPCRs)

Now it's time to expand even more on the signalling pathways covered here and here! Yup, there's even more stuff that you're going to need to know. If you're not familiar with the signalling pathways that have already been covered, I suggest that you look back on these before proceeding or you're going to be lost in the alphabet soup to come.

Stretch can activate some G-protein coupled receptors, such as the AT₁ (angiotensin) receptor. Furthermore, some of the signalling molecules in the G-protein coupled receptor signalling pathway can increase the opening probabilities of the SGCs mentioned above. DAG (diacylglycerol) can bind to and increase the opening probability of TRPC3 and 6, whereas IP₃ does the same for TRPM4.

Autocrine and Paracrine Signalling Molecules

Smooth muscle can also release some mediators that can act in an autocrine (on the same cell) or paracrine (on neighbouring cells) fashion.

Phospholipase A (PLA₂) is a membrane-bound enzyme that is activated by stretch. When activated, it catalyses the formation of arachidonic acid, which can be further broken down to form 20-HETE and thromboxane A2 (TxA₂)- yup, the same TxA₂ mentioned in PHAR3303. These can diffuse out of the cell and bind to receptors (such as the G-protein receptors mentioned above) on the same cell or on neighbouring cells. Other signalling molecules that may act in this fashion include sphingosine-1-phosphate (S1P), UTP and ATP.

Describe DI induced bronchodilation and its relevance to asthma and COPD

DI = deep inhalation. When we take in a deep breath, it reduces bronchoconstriction. That's why it's so much easier to exhale after we take a deep breath in first. In patients with asthma or COPD, this mechanism may not work- a DI may cause no change, or maybe even bronchoconstriction.

Explain how length-adaptation and stretch induced dilation might be due to rearrangement of actin and myosin filament
Describe the labile nature of actin and myosin in smooth muscle

Smooth muscle is very adaptable. If you pin it out at a longer length, it will adapt so that that longer length becomes its new optimum length for contraction. If you pin it out at a shorter length, it will likewise adapt so that that shorter length becomes its new optimum length. Interestingly enough, no changes in calcium or myosin light chain phosphorylation are associated with this phenomenon, so something else must be at play.

That something else, believe it or not, is the ability of smooth muscle to add or remove contractile units (a property that is unique to smooth muscle). When smooth muscle contracts, it assembles its thick filaments (i.e. myosin filaments). This may seem counterintuitive, but when myosin is phosphorylated (as happens during contraction), it is more stable, which may help with polymerisation. Stretch triggers disassembly of these filaments so that they can reassemble at a new length. We're still not sure on all of the details, but the end result is that a muscle that is adapted to a shorter length will have fewer myosin filaments, whereas a muscle that is adapted to a longer length will have more myosin filaments.

Actin filaments are also important. Contraction triggers polymerisation of actin as well as myosin. Inhibiting the polymerisation of actin will also reduce the amount of force that can be produced.

Of course, it's not that simple in vivo. As loads on muscle are often oscillating (such as in airway muscle where you are breathing in and out all the time), the muscle may never be able to finish adapting to any length. This may be why airway smooth muscle often relaxes with oscillatory loads (such as the loads placed on it during regular tidal breathing).

There's also another phenomenon to take note of called shortening inhibition. Shortening inhibition basically means that the longer you leave a muscle contracted, the less able it is to contract.

Define Latch

Latch is a state in which the cross-bridges are attached, but are not cycling. We're still really not sure about how this happens, though: maybe the cross-bridges are dephosphorylated or something like that, preventing them from releasing, or maybe this is due to the polymerisation of actin filaments after contraction. In any case, the latch state is probably the reason why smooth muscle can maintain tone without using up a lot of ATP, despite smooth muscle contraction being less efficient than in other muscles (smooth muscle is consistently polymerising and depolymerising its filaments, and that shit takes energy).