Synaptic Transmission and NMJ

Hello All,

I apologize for not having time to cover the third turningpoint question in the lecture.  I know it is a difficult question and I have addressed it below.  I have also included a few additional questions that you all have sent my way:

1)  One of the slides you gave us showed the different types of Neurotransmitters (ex: Biogenic, Cholenergic, Purinergic, etc). Should I memorize the different types of neurotransmitters or was it there just for our reference?

 
As I mentioned in the lecture, I was introducing you to the different types of neurotransmitters and the variety that exist.  You are expected at this point to know about Acetycholine, Epinephrine, and Norepinephrine where they are important and the others you will cover in greater detail next semester during a neurotransmitter lecture given by Dr. Meisenberg.
 

2)  Quick question, did you want us to know the details for vesicle binding (t-SNARES,etc), or just know that it is mediated via synaptotagmin? 

Also as I mentioned in lecture, there are a lot of details regarding exocytosis and I do not expect you to know all of the details (they are continuing to change as research of them are VERY active), but I do expect you to know that Ca2+ binds to synaptotagmin to initiate the process.

3)  Would you please expain the last turning point question in the lecture from today's lecture?

Could you please explain the 3rd question from the lecture that we didn't go over? What is the "steady-state level" and how does Na+ channels in the muscle membrane adjacent to the endplate desensitize the ACh receptor?

I understand this is a difficult question, but one of your classmates did a great job of explaining what is actually happening, so I am going to quote their reasoning to provide this explanation: 

"So if Ach is constantly present in the junctional synapse, there will be elevated binding to the receptors. Therefore, the sodium channels will constantly be stimulated to open. Now it isn't until the K+ have closed that the sodium channels will be released from their inactive state, and since the potassium channels take longer to close, there isn't much time to restore the system to a ready state due to constant stimulation."

Indeed, constant release of ACh from the presynaptic neuron causes constant binding of ACh to the postsynaptic receptors.  This will then cause the postsynaptic receptors to continuously depolarize the motor endplate and causing the voltage-gated Na+ channels to remain inactivated.  Subsequent to this, the nAChR becomes desensitized and eventually the membrane repolarizes (and the Na+ channels go to closed), but as the nAChR are desensitized, the membrane can then not depolarize.  



4) 7.  Which of the following statements about synaptic transmission at the neuromuscular junction is true?
  A.  It is enhanced by high levels of cholinesterase
  B.  It is caused by an influx of potassium ions through the muscle membrane
  C.  It is depressed by increased parasympathetic nerve activity
  D.  It is produced by the release of acetylcholine from the alpha motorneuron

Why can't it be A or C.

Acetylcholinesterase is the enzyme that breaks down Acetylcholine in the junctional cleft.  Therefore, high levels of cholinesterase will decrease the synaptic transmission not enhance it.

Parasympathetic nerve activity is part of the autonomic nervous system that influences the non-voluntary parts of the body.  Skeletal muscles are activated by the somatic nervous system (voluntary), and is therefore not activated or inhibited by the parasympathetic nervous system.  The parasympathetic postganglionic neurons will innervate things like the heart, the gut, the lungs, but not the skeletal muscles.

5) So at the neuromuscular junction there are nicotinic receptors, which are parasympathetic receptors?

At the muscle end plate, acetylcholine (ACh) causes the opening of which of the following?

  A.  Na⁺ channels and depolarization toward the Na⁺ equilibrium potential

  B.  K⁺ channels and depolarization towards the K⁺ equilibrium potential

  C.  Ca²⁺ channels and depolarization towards the Ca²⁺ equilibrium potential

  D.  Na⁺ and K⁺ channels and depolarization to a value halfway between the Na⁺ and K⁺ equilibrium potentials

  E.  Na⁺ and K⁺ channels and hyperpolarization to a value halfway between the Na⁺ and K⁺ equilibrium potentials

The answer is D?

I do understand some confusion.  The parasympathetic nervous system does utilize the same TYPE of receptor as the somatic nervous system.  However, the nAChR is the receptor located at the junction of the preganglionic and postganglionic nerve fibers within the ganglia.  In the somatic nervous system this same receptor is located at the neuromuscular junction.  The receptor is the SAME receptor and fluxes the same ions (both Na+ and K+ to a membrane potential that is halfway between their equilibrium potentials which is why + ions come INTO the cell to depolarize the membrane potential).  In the parasympathetic nervous system this causes the activation of an action potential in the postganglionic neuron and in the somatic nervous system this causes an endplate potential and subsequently an action potential along the sarcolemma of the skeletal muscle cell.

6) Could you please explain this question from NMJ lecture. I was wondering why choice A is wrong as opposed to choice B? 

8.  Periodic hyperkalemic paralysis is characterized by high potassium concentration and muscle weakness.  Which of the following is likely to cause muscle weakness as a result of increased extracellular potassium concentration?

  A.  Hyperpolarization of muscle cells

  B.  Inactivation of sodium channels in muscle cells

  C.  Increased release of neurotransmitters from alpha motorneurons

  D.  Decreased potassium conductance in muscle cells

  E.  Increased duration of action potentials produced by alpha motorneurons

Remember from the action potential (and membrane potential) lectures that an increase in extracellular K+ concentration can cause the depolarization of the membrane potential.   If you increase the extracellular K+ concentration (even slightly), the driving force for K+ to leave the cell is slightly decreased.  Since the equilibrium potential is a value that corresponds to this driving force in a number form, that number becomes a small number.  Since that number is below zero, a smaller number below zero would be depolarized (closer to zero).  [Put some numbers to it and calculate the equilibrium potential for K+ with an intracellular concentration of 150mM and an extracellular concentration of 5mM, then change the extracellular concentration to 10mM].  Therefore, since the resting membrane potential depends quite heavily on the equilibrium potential for K+, and the repolarization phase of the action potential depends quite heavily on the equilibrium potential for K+, if that changes the resting membrane potential depolarizes and the repolarization phase of the action potential does not occur as readily.  Remember also that the voltage-gated Na+ channels NEED the membrane to repolarize to recover from inactivation.  Therefore, if the membrane has a difficult time repolarizing (as is the case with high extracellular K+), then the Na+ channels get stuck in their inactivation phase and cannot initiate any subsequent action potentials.