Synaptic Transmission and NMJ

Here are a variety of questions regarding synaptic transmission and the neuromuscular junction to clear up the confusions you have.  

Please note that if you had trouble with membrane potentials or action potentials on the last exam and the concept is not covered in the review today, please feel free to contact me and we can set up a time to discuss the concepts you found difficult.  As I mentioned before, membrane potentials and action potentials are very important basic concepts that are important to understand for the rest of your medical career, so the sooner we can clear up any confusions you may still have regarding them the better!

1.  It was mentioned that glutamate receptors are predominant in the CNS. Are acetylcholine receptors the major excitatory postsynaptic receptor for the peripheral nevous system? What about acetylcholine receptors in the central nervous system? 

I guess you could say that acetylcholine is the major excitatory neurotransmitter in the PNS.  I've never really heard it referred to as that, but indeed it is what causes all of the depolarization at the nAChR at the pre-post ganglionic neuronal connection for the autonomic nervous system and at the neuromuscular junction.  ACh does, however, provide some inhibitory action through muscarinic AChR in the parasympathetic ANS, so that is probably why it is not referred to as only excitatory.  There really is not ACh being released in the CNS, except if you consider the paravertebral chain (where the pre-post synaptic ganglions connect for the sympathetic ANS) to be within the CNS.  It is located close to the spinal chord, but it is my understanding that the CNS only includes the brain and spinal cord and everything else is PNS, which would mean that ACh is only released in the PNS.

2.  Is the difference between the endplate potential and action potential just the the location where these action potential are found? So, it's called endplate potential because the post synaptic receptor are found in the muscle cell. Are there anymore distunguishing features?

Endplate potential is the change in membrane potential JUST AT the motor endplate (remember this is differently named than excitatory post-synaptic potential that happens in the CNS).  When that change in membrane potential activates the voltage-gated Na+ and K+(more slowly) channels located surrounding the motor endplate, THAT is when it is transferred into an action potential (as by definition the action potential in the muscle involves those two channels and is an all-or-none event).  My guess is the nomenclature came from naming the postsynaptic side (the muscle) the motor endplate, therefore the potential change there would be a potential of the endplate.  Further research within the CNS would have discovered that not all synaptic transmission is the exact same as this and therefore they would require additionally distinguishing names.  That, however, is just MY hypothesis as why it is named that is not entirely clear.

3. Another question regarding the practice problems:
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

I understand why B is correct. But why can't D also be correct. Isn't it true that the postive charge from the increased potassium concentration n the extracellular space preventing the intracellular K to move out of the cell at the plasma membrane?

Remember that conductance has to do with the channels themselves being open and allowing for the movement of the ion.  (slide 26 from Membrane Potentials: 

 

For each ionic species, the driving force is the difference between equilibrium and the membrane voltage (i.e. Vm – Eion).  At any voltage, the current due to a given ion is then:

Iion = gion (Vm – Eion)

Where:  I = current

  g = conductance

  Vm = membrane potential

  E = equilibrium potential

Therefore, a decreased DRIVING FORCE (Vm - Eion) for K+ to leave the cell would definitely occur, and that would effect the current of K+, but not necessarily the conductance.

4.  Do we need to memorize the different types of neurotransmitters and their classifications (biogenic amines, etc.) for the exam?

This question ALWAYS comes up.  NO, you do not need to memorize the different types of neurotransmitters and their classifications or what receptors they precisely are named to answer.  However, next semester when you review neurotransmitters with Dr. Meissenberg, he WILL require that you memorize these details, so if you are exposed to them and work with them now and then learn them again then it should be easier to memorize them upon second exposure.  At this point, if I talk about a neurotransmitter and/or receptor I will give you the name and action and I expect that you know that the movement of Cl- into the cell or K+ out of the cell would produce an IPSP, or that the movement of Na+, K+, or Ca2+ into the cell would produce an EPSP.

5.  You mentioned during lecture that K+ fluxes into the cell during hyperpolarization, but doesn't it flux out of the cell during hyperpolarization? This was mentioned while discussing muscarinic AChR in cardiac muscle.

I believe you are combining two things that I said, but possibly not so let me clarify:

The movement of K+ out of a cell would cause hyperpolarization.  This would occur if made a cell more permeable to K+ at rest.  In the cardiac system, the activation of the muscarinic AChR would cause a signalling cascade of events that results in the opening of a K+ channel that is named the 'Inward Rectifier K+ channel'.  It moves K+, however, down its electrochemical gradient OUT of the cell, thereby hyperpolarizing the membrane.  This is demonstrated on slide 14 of the Synaptic Transmission and NMJ lecture. 

The movement of K+ into a cell would cause depolarization.  This occasionally happens when you open the nicotinic AChR because the driving force through that channel (from rest) is for depolarizing charges (+ charges) to move into the cell.  Because that channel can allow both Na+ and K+ to move through it, if there is a K+ near to the channel when it opens, it will flow through that channel into the cell, thereby contributing to the depolarization of the membrane through that channel.

6. I was just wondering...the Calcium that is entering the VG channels of the motor neuron, is this the same Calcium that had been triggered to be released from the endoplasmic reticulum in the IP3/DAG pathway (from Dr. Meissenberg's cellular signaling lectures)?

NO!  The calcium that Dr. Meissenberg is talking about is INTRACELLULAR Ca2+, what we are talking about flowing through the voltage-gated Ca2+ channel from the extracellular space into the axon terminal is EXTRACELULAR Ca2+.  Now, Ca2+ IS Ca2+, so it is the same molecule, but it is a different source of Ca2+ than what Dr. Meissenberg was talking about which is an intracellular store of Ca2+.  

What we saw in class today is that there is also endoplasmic reticulum Ca2+ that is released in the skeletal muscle similar to that released in the IP3/DAG pathway, but it is released by a different mechanism (the opening of the DHP Receptors that opens the Ryanodine receptors releasing the Ca2+ from the endoplasmic reticulum which in this case is called the sarcoplasmic reticulum.)

What we will also see in class on Friday, that smooth muscles actually use BOTH of these pathways to harness Ca2+ in order to create contraction...more to come tomorrow!

7. I just wanted clarification on where exactly are the enzymes responsible for breaking down NTs.  It is my understanding that they are located in the presynaptic membrane, post synaptic membrane and synaptic cleft or junctional cleft (for NMJ).   If this is the case, which of the three is responsible for the breakdown of the NT?  Do they all function simultaneously?

Indeed, in some systems the enzymes are located on the presynaptic membrane, some on the post, and some soluble within the synaptic cleft.  ALL available enzymes that are targeted for a given neurotransmitter would be responsible for the breakdown of the given neurotransmitter and if there were multiple enzymes available to breakdown a given enzyme, they would certainly work simultaneously.  The details of specific enzymes (other than acetylcholinesterase) will be covered in the neurotransmitter lecture by Dr. Meissenberg next semester.

8. I'm getting a bit confused on summation of postsynaptic potentials. This is my understanding: graded potentials aggregate to produce an AP at axon hillock of neuron. AP travels down the axon, opens Ca2+ gated channels, Ca2+ rushes in, vesicles bind and release neurotransmitter. The neuron's job is now done.

Essentially yes, the job of that neuron is now down...but remember that all of the things that will happen in the NEXT neuron were what happened at the dendrites to this neuron.  The IPSPs and EPSPs ARE the graded potentials that aggregated to produce the AP at the axon hillock of that neuron.  When we are taking about the neuromuscular junction, that is where it gets a bit more specific.

Now, what do graded IPSPs and EPSPs have to do with anything? AP was relayed across the neurmuscular cleft in a chemical method. That should result in an action potential or inhibitory effect on the postsynaptic cell. 

As I mentioned above, the IPSPs and the EPSPs ARE the graded potentials that aggregated to produce the AP at the axon hillock of the neuron.  In this case we will consider that that neuron was a motor neuron (but know there are MANY neuron to neuron connections within the CNS and much of the details of the tracks within that system that are known within research will be covered next semester in the Neuro unit).  The chemical synapse at the neuromuscular junction, however, is just a bit more specific in that it creates a similar graded potential in the muscle, but we call this an endplate potential (covered above in question #1), and due to the fact that it is solely excitatory (always releases ACh that bind to nAChR that allow for the influx of + charges to depolarize the motor endplate), it will ALWAYS activate the surrounding voltage-gated Na+ and K+ channels activating an action potential on the postsynaptic cell (the muscle cell).

What the slide seems to imply is that individual receptors are causing graded potentials inside the post synaptic cell which then summate to excite/inhibit the cell. Whatever happened to one AP in presynpatic cell leads to one AP in post synaptic cell? 

Within the CNS, the graded potentials (both excitatory/EPSP or inhibitory/IPSP) summate to either trigger an action potential at the axon hillock, or to not summate enough to reach threshold to trigger an action potential.  At the NMJ, however, as stated above, it is always excitatory and it is enough excitation produced on the motor endplate that you will trigger an action potential in the postsynaptic cell or the muscle cell.

Are there, perhaps, multiple nerotransmitter types being stored in vesicles that could maybe account for a pre-syn AP not having enough (of a certain type) to excite a post-syn cell to produce an AP of its own? If that is the case, how is the cell ever able to get a proper response from a mixed neurotransmitter package if it can have both inhibitory and excitory components? 

NO, there are ONLY a single type of neurotrasnmitters in a single vesicle (at least not yet discovered).  However, in some synapses there are multiple types of vesicles (each containing there own type of neurotransmitter).  Remember, it is the RECEPTOR on the postsynaptic side that relays the information from those neurotransmitters.  Therefore, there could be multiple information happening at one single synapse.  For example, you could have a simple excitatory neurotransmitter like glucose, but also within that synapse could be released a peptidergic neurotransmitter that could cause a metabotropic response that is a much longer-lived response and may support the initial excitation of the membrane.  Much of the details of these synergistic events are not yet worked out within the science of our CNS.  However, as you can imagine they could work together to make action potentials occur and/or to make the response at a synapse work better or worse.  You will cover some of this next semester, but much of the more known details of these types of manipulations are beyond the scope of basic medicine and not fully understood within the scientific research as well...looks like there are PLENTY of fellowships waiting for you!