Excitation-Contraction coupling & contraction in smooth muscle.  

Excitation-Contraction Coupling:  Some of the most important differences between skeletal muscle and smooth muscle occur in excitation-contraction coupling.  One element that is the same between the two forms of muscle is that calcium plays a "starring" role.  Unfortunately, that is about the extent of the similarities.  Smooth muscle differs in: 

    • the source of the calcium (relying both on extracellular and intracellular sources). 
    • how the release of the calcium into the intracellular space is accomplished (the control), and
    • how the calcium is used to initiate the contraction.  

A quick review of excitation-contraction coupling in skeletal muscle:  

    The sarcoplasmic concentration of calcium in skeletal muscle is kept very low by the action of Ca-ATPases which remove the calcium and sequester it in the sarcoplasmic reticulum.  When an action potential depolarizes the muscle cell membrane, it also travels into the body of the cell via the t-tubules.  The t-tubules are one component of the triads, which are composed of the t-tubule surrounded by the terminal cisternae of two parts of the cell's S.R.  With depolarization of the t-tubule, there is a conformational change in the dihydropyridine receptor, which "pulls" the ryanodine receptor on the S.R. membrane open.  This allows the calcium to enter the sarcoplasm and diffuse to the contractile apparatus.  Once at the contractile apparatus, the calcium binds to troponin.  The troponin undergoes a conformational change and pulls the tropomyosin away from the actin active site.  Once the active site is exposed, the myosin head (which has a strong affinity for the active site) binds and the cross bridge cycle begins.   

Sources of Calcium in smooth muscle cells

Unlike skeletal muscle, smooth muscle is dependent on two sources of calcium in order to initiate contraction.  These two sources are: 

    • calcium sequestered in the S.R. of the smooth muscle cell. 
    • extracellular calcium that can enter the smooth muscle cell via calcium channels on the membrane of the smooth muscle cell.  

There are two points to keep in mind about the sources of the calcium in smooth muscle contraction:  1)  difference mechanisms are in place to control these sources - what allows calcium to enter from one source may not have any direct effect on the other source of calcium; and 2) For most contractions of smooth muscle (particularly longer-lasting contractions), both sources of calcium are used to maintain the contraction.   In the next section, we'll discuss the different control mechanisms that allow calcium entry into the smooth muscle cell. 

Control of calcium release in smooth muscle cells

As noted before, the release of calcium from the S.R. is controlled independently of the entry of calcium from extracellular sources.  The first slide summarizes how calcium is released from the S.R. of the smooth muscle cell.  Unlike skeletal muscle, which requires depolarization of the cell membrane and t-tubules, smooth muscle uses second messenger systems to open the calcium channels on the S.R.  Receptors on the smooth muscle membrane for such ligands as endothelin (released as a paracrine agent), Epinephrine (released as a hormone or a neurotransmitter), and Ach (released as a neurotransmitter) connect to the Gq protein and lead to the production of inosital triphosphate (IP3).   The IP3 is then directly responsible for opening the calcium channels on the S.R. membrane, allowing the calcium to enter the cytoplasm of the cell.   There is one important consequence of this process:  Unlike skeletal muscle, smooth muscle can be made to contract in the absence of an action potential.  

As you might guess, the calcium enters through calcium channels found on the smooth muscle cell membrane. 

There are both ligand-gated calcium channels and voltage-gated calcium channels present on the smooth muscle membrane.  The ligand-gated channels open when a specific chemical binds to the receptor and causes the calcium channel to open.  The influx of calcium that occurs causes membrane depolarization (calcium having a valence of +2).  This depolarization then allows the voltage-gated calcium channels to open, furthering the influx of calcium and leading to an action potential.  Since smooth muscle cells do not have voltage-gated sodium channels, the action potential generated is the result of the calcium influx.  Thus, we often say that smooth muscle shows a "slow action potential" which is synonymous with the term "calcium spike".  Note that the term "slow action potential" is not a general term in physiology - it refers very specifically to an action potential that is the result of a calcium influx as opposed to a sodium influx.   The calcium that enters the cell from extracellular sources also diffuses into the cytoplasm of the cell and participates in smooth muscle contraction.  An important note:  prolonged contraction of smooth muscle requires extracellular calcium.  The S.R. of the smooth muscle cell does not contain enough calcium to maintain contraction for long periods of time.  

How calcium starts the contraction process in smooth muscle:

If you'll recall from the discussion of the biochemistry of smooth muscle cells, troponin is not found in smooth muscle.  Additionally, the tropomyosin found in smooth muscle does not cover the actin active sites, although it is still associated with the thin filament.  Furthermore, at rest the myosin head does not have the high affinity for the actin active site that we see in skeletal muscle.  It is obvious, then, that smooth muscle must use the calcium in a very different way to initiate contraction.  

This is where the calcium-binding protein calmodulin and the myosin light chain kinase come into play.   Once we have increased the intracellular calcium  levels (regardless of the source of the calcium), the calcium binds to the calmodulin, which is very close to the contractile apparatus.  Once four Ca++ ions bind to the calmodulin, the Ca-calmodulin complex binds to the myosin light chain kinase and activates it.  Myosin light chain kinase (MLCK) is an enzyme that phosphorylates one of the two myosin light chains associated with the myosin head.  The MLCK hydrolyzes ATP and takes the inorganic phosphate (Pi) from the ATP and puts it on the myosin light chain.  Once the myosin light chain is phosphorylated, the myosin head (probably because of the conformational change produced by phosphorylation) develops a high affinity for the actin active site and binds readily to it.  Remember that the active site is not covered at rest - smooth muscle relies on the low affinity of the un-phosphorylated cross-bridge to keep the two apart.  

The contractile process in smooth muscle

As we noted above, skeletal muscle already has a very nice contractile mechanism for force generation - the interaction between the thick and thin filaments.  Smooth muscle, knowing a good thing when it sees it, uses the exact same mechanism for force production and shortening. 

The process of relaxation in smooth muscle:  Smooth muscle will continue to contract as long as there is calcium bound to the calmodulin and the myosin light chains remain phosphorylated.  Once the stimulus for the release/entrance of calcium has been removed, a series of Ca-ATPases will begin to move the Ca++ back into the S.R. or out of the cell.  As the intracellular calcium levels drop, the calcium will leave the calmodulin.  Once the Calcium-calmodulin complex is no longer present, the Myosin light chain kinase is inactivated.  

There is still once more step before relaxation can truly begin - the myosin light chain that was phosphorylated by the MLCK must be dephosphorylated by the myosin light chain phosphatase mentioned previously.  Once the myosin light chain is dephosphorylated, the myosin head no longer has significant affinity for the actin active site and relaxation ensues.  

A special note:  The myosin light chain can be dephosphorylated at any point within the crossbridge cycle.  The cycle will continue as normally (i.e. it doesn't stop right in the middle just because the light chain isn't phosphorylated anymore).  However, the cycle will proceed very slowly.  Once the myosin head dissociates from the active site, a new cycle cannot begin.  

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