Review of the process in skeletal muscle:  Skeletal muscle has a well-defined system for producing excitation of the skeletal muscle cells.  

An alpha-motoneuron innervates the muscle cell, forming a neuromuscular junction.  The presynaptic (neuron) side of the NMJ is specialized to allow the release of acetylcholine from the terminal in response to an action potential.  The acetylcholine then diffuses across the synaptic cleft to bind to a acetylcholine receptor found at the motor endplate, a specialized piece of membrane that comprises the post-synaptic side of the NMJ.  The binding of Ach to its receptor causes the entrance of sodium into the muscle cell, leading to the end-plate potential.  Since there are no voltage-gated sodium channels at the motor endplate, the sodium must diffuse to neighboring membrane to activate those voltage gated sodium channels.  This will lead to an action potential (typical fast sodium spike, as described in the action potential lectures - for a quick review, click here).  Under normal conditions, skeletal muscle does not contract unless an action potential depolarizes the cell membrane first.  

The process in smooth muscle cells:  Smooth muscle, like skeletal muscle, needs some signal to begin contraction.  However, there are many signals that lead to contraction in smooth muscle, not just one (acetylcholine released from the motoneuron) as in skeletal muscle.  These differences will be discussed/illustrated in the next several animations, and then summarized at the end of this section. 

Neural excitation of smooth muscle:   

    Innervation of smooth muscle:  The nerves innervating smooth muscle can arise from many different sources, unlike the situation in skeletal muscle.  Several places in the body, e.g. the GI tract and the trachea) have what amount to largely independent nervous systems that control the smooth muscle in these areas.



These nerve plexuses are referred to as intrinsic innervation (since the innervation is intrinsic to the organ containing the smooth muscle).  The neurons of these plexi can be sensory, motor (efferent), or what amount to interneurons, neurons which relay information from one neuron in the plexus to another neuron in the plexus.  Intrinsic innervation is important for our survival because it means that the functioning of the smooth muscle in these areas can continue even following damage to the central nervous system.  For example, the intrinsic innervation of the GI tract allows a person to continue to digest their food normally, even following transection of the spinal cord.  

      Most smooth muscle, even that in areas that have intrinsic innervation, also receive inputs from the central nervous system, referred to as extrinsic innervation.  This input generally arises from the autonomic nervous system.  Most smooth muscle receives opposing inputs from the sympathetic and parasympathetic parts of the ANS, although the degree of innervation may vary.  For example, vascular smooth muscle receives little or no parasympathetic innervation while it receives a lot from the sympathetic system.  In systems where we have both intrinsic and extrinsic innervation of the smooth muscle, the intrinsic nervous system is usually the most direct controller, the extrinsic innervation has only weak direct effects on the smooth muscle, instead acting primarily to modify the activity of the intrinsic system.

Interactions between the nerve and smooth muscle cell:    Regardless of the source of the innervation (intrinsic or extrinsic) the junction between the nerve and the smooth muscle cells are the same. Unlike skeletal muscle, there is no specialized connection between the nerve fiber and the smooth muscle cell.  

The nerve fibers essentially passes "close" to the smooth muscle cells and releases the neurotransmitter (which is not restricted to acetylcholine - see below) from swellings in the fiber, called varicosities.   The neurotransmitter released from the varicosity has a considerably longer distance to travel than the acetylcholine released at an NMJ does.  In addition, the neurotransmitter can bind to any one of the nearby smooth muscle cells, a flexibility not found in the NMJ. 

The chemicals that influence smooth muscle cells:  As you'll recall, there is only one neurotransmitter released at the neuromuscular junction - acetylcholine.  In contrast, many different neurotransmitters can be released from the many different nerves that innervate smooth muscle cells.  As a further contrast from skeletal smooth muscle, some of the neurotransmitters/chemicals that act on smooth muscle directly inhibit it, causing relaxation.  Skeletal muscle receives no direct inhibition (you'll never see an ipsp in a skeletal muscle cell) and relaxation occurs by inhibiting the alpha-motoneuron that innervates the muscle cell.  The following is a list of the major chemicals that acts on smooth muscle and their general effects on smooth muscle.  It is not an exhaustive list - but it covers many of the major players.  

    • Acetylcholine:
      • released by parasympathetic neurons & the some neurons in the intrinsic innervation of gut, trachea. 
      • direct effect is to cause contraction via muscarinic receptors (connected to G protein - we'll discuss how this can cause contraction later). 
      • in vasculature, a few other places, Ach can indirectly (i.e. acting through a secondary agent) cause relaxation of smooth muscle.  
    • Epinephrine (generally a hormone) /norepinephrine (generally a neurotransmitter)
      • Released as a neurotransmitter by the sympathetic system & as a hormone by the adrenal medulla in response to sympathetic activation.  
      • Remember that we have two major kinds of receptors here - the alpha's and the beta's. 
      • Because the different receptors do different things inside the cell, the effects vary depending on what receptor is found on the smooth muscle cell. 
      • The exact effects will depend on what system you are in - that information will be covered in each of  the different systems. 
    • Nitric oxide (NO)
      • Released by neurons of the intrinsic nervous system of the gut & trachea, as well as CNS neurons. 
      • Is also released by the endothelial cells of the vasculature and by cells of the immune system. 
      • Formed when the enzyme nitric oxide synthase takes arginine into NO and citrulline.
        • production of NO is controlled by the presence of calcium in the neuron/cell - NO may not be stored in vescicles.  
      • Very lipid soluble - diffuses out of neuron  and into surrounding cells without benefit of receptor. 
      • In target cells, activates the production of cGMP.  
      • NO is the major inhibitory neurotransmitter causing relaxation of smooth muscle in the GI tract, and it is a significant contributor to the relaxation of vascular smooth muscle (Ach causes release of NO in the vasculature).  

The following chemicals are of particular interest in the vascular system - they may or may not have any effects on smooth muscle in any part of the body.  Note, however, that that does not mean they don't have additional effects on other tissues in the body. 

    • Prostacyclin
      • Also known as PGI2  - requires cyclo-oxygenase and arachidonic acid for production. 
      • in the cardiovascular system, is released by the endothelial cells into the vicinity of the smooth muscle cells. 
      • Binds to a cell surface receptor (IP) that leads to the production of cAMP.  
      • Like the cGMP made by NO, cAMP tends to cause relaxation of smooth  muscle (we'll talk about how later).  
    • Endothelium-derived hyperpolarizing factor (EDHF)
      • Identity unknown, although it is suspected of being another metabolite of arachidonic acid metabolism in cells. 
      • Works through a potassium dependent mechanism. 
      • causes hyperpolarization and relaxation of vascular smooth muscle
      • In humans, believed to be the major contributor to relaxation of vascular smooth muscle - blocking NO and prostacyclin only gets rid of about 25% of the relaxation seen in response to certain stimuli.  
    • Adenosine
      • may be a neurotransmitter in some systems or just a metabolite that accumulates with activity. 
      • causes inhibition and relaxation of vascular smooth muscle. 
    • Endothelin (ET)
      • actually a family of three 21 amino acid peptides (ET-1, ET-2, and ET-3). 
      • like many peptides, it is formed in the endothelial cells in a "big" form (they really do call it big-endothelin-1(2 or 3)) and then cleaved down to the active (21 amino acid) form. 
      • Causes contraction of vascular smooth muscle (one of the most potent found in the human body). 

The post-synaptic membrane of smooth muscle:  We have now looked at the differences between the release of the neurotransmitter and the substances that can influence smooth muscle contraction.  The next step in the process is the neurotransmitter diffusing across the "synaptic trough" and getting to the post-synaptic membrane of the smooth muscle.  

The important features:   

    • the synaptic trough found at smooth muscle is considerable bigger than we see at the neuromuscular junction of skeletal muscle. 
    • the neurotransmitter is "free" to interact with any one of several smooth muscle cells because the synaptic trough is not as isolated as we saw in skeletal muscle. 
    • there is nothing equivalent to the motor endplate in smooth muscle, therefore receptors for the neurotransmitters are located throughout the smooth muscle membrane.
    • there are receptors for multiple neurotransmitters - of the list of chemicals above, the only one without a receptor is nitric oxide because it is so lipid soluble that it doesn't need a receptor - it goes straight into the smooth muscle cell.  

There is one MAJOR difference between smooth muscle and skeletal muscle that we need to consider here:  Unlike skeletal muscle, smooth muscle can be made to contract by hormones and paracrine agents. 

Smooth Muscle Cells can also be activated/inhibited by hormones:  Smooth muscle cells are not solely dependent on innervation for their inputs.   Many hormones are also capable of activating (or inhibiting) smooth muscle. 

   Receptors are also concentrated on the blood side of smooth muscle cells.   Smooth muscle cells often receive their innervation on one side and their blood from the other side.    All we need to do is put receptors for the hormone on the smooth muscle cell (which they are quite capable of doing), and we have a smooth muscle cell that will respond to the hormone.   You're already familiar with one example of this:  the epinephrine released from the adrenal medulla will find receptors on certain smooth muscle cells and can cause contraction or relaxation, depending on the receptor present on the cell membrane.   In the vascular system, there are several hormones that can cause or inhibit contraction of the vascular smooth muscle.  One worth special mention is angiotensin and its derivative angiotensin II.  The GI system as well has a full complement of hormones that induce/inhibit smooth muscle contraction.  

Smooth muscle cells can also be activated or inhibited by agents released into the extracellular fluid by neighboring cells:  Such agents are called paracrine agents.  Activation and inhibition of smooth muscle by paracrine agents is a very common in the body - particularly in the vasculature.  

 In the picture, you can see the endothelial cells lining the vessel that has been cut in cross section.  The smooth muscle cells of the vasculature lie in the layer underneath the endothelial cells (away from the lumen).  The blood in the vessel flows directly over the endothelium.  The endothelial cells are stimulated (depending on how fast the blood is flowing and what substances are in the blood) to release several paracrine agents into the space between the endothelial cells and the smooth muscle cells.  The substances include NO, prostacyclin, and EDHF when the blood flow is very fast (each of these substances will then cause relaxation of the smooth muscle, allowing the lumen of the blood vessel to increase in radius (vasodilation) and slowing down the blood), or endothelin (when the blood flow is low, the pressure high, or certain chemicals are found in the blood).  Endothelin causes contraction of the smooth muscle, making the lumen of the blood vessel smaller (vasoconstriction). 


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