– Modification of transmission means either increase or decrease transmission.
– Increase transmission means more muscle contraction or [muscle spasm], decrease transmission means less muscle contraction (paralysis ).
Substances or drugs that increase transmission:
1. Increase release of acetylcholine: by black widow spider venom. it causes explosive release of acetylcholine in neuromuscular junction, and by this acetylcholine will stay long time in the receptor, result in muscle spasm (death from suffocation because diaphragm is continuously contracted, so, no respiration).
2. Prevention of the destroy (in activation) of the acetylcholine, by inhibiting acetylcholine esterase, this inhibition is either (reversible) (i.e. the enzyme inhibited for hours or sometime and then comeback active and work (destroying ACH), or irreversible (i.e. the enzyme is permanently in active).
· Reversible = e.g. neostigmine and physostigmine.
· Irreversible = e.g. organophospharate compounds may be used as pesticides or in wars like nerve gas .
· When reversible inhibition of ACH esterase occur, it just increase the level of ACH in neuromuscular junction for sometime, but, when irreversible inhibition occur it will cause sustained excitation of muscle lead to spasm of diaphragm (then no respiration and death).
· ACH = acetylcholine
Substances that decrease transmission:
1. Substances which block release of ACH = e.g. clostridium botulinum toxin. It is toxin produced by bacteria called clostridia usually present in cans .
· It cause less release of ACH, then no muscle contraction, then paralysis of muscle , paralysis of muscle of limbs will not kill the person, but, paralysis of respiratory muscle (like diaphragm) will suffocate person and will die…. (bye)
2. Block of ACH receptor by a substance similar to ACH in structure but have no function (just binding with receptor) so that when ACH come to bind with receptor it will find it occupied, so, as to say ACH not working.(this substance will occupy the receptor competitively)
· This situation will also make muscles paralyzed and death from (diaphragm paralysis).
· E.g. on this = curare; ancient Indians used this substance in hunting by applying this substance on the head of arrow that will hit the animal, so that making animal paralyzed and essay to be catched.
3. Destroy of ACH receptors: in some cases body may fight himself by immune system and destroy some tissues by producing antibodies against them, if antibodies was against ACH receptors, then the receptors will be destroyed, this disease is called [myasthenia gravis] and it is auto-immune disease .
· Here we have less number of receptors, and then less number of channels that transmit Na+, so threshold is hard to reach.
In this disease, eyelids mainly first affected, so we have droped eyelids.
· How treat this disease? We have to over come the reduced number of receptors by increasing acetylcholine so that ACH is available for larger period and the few receptors stay excited by ACH for more period and the result is improvement in muscle contraction.
· How to increase ACH in junctions?
Answer: by giving physostigmine or neostigmine (reversible inhibitors of ACH esterase).
Comparison between synapses & Neuromuscular junctions
Before discussing this subject we need to know some details on synapse:
1. They are meeting of tow or more neurons and also consist of pre and post synaptic membranes and also release neurotransmitter which binds with specific receptors on post synaptic membrane changing membrane permeability to ion.
2. In synapses it is possible that multiple nerve branches from different axons meet together on single neuron body.
3. In order that postsynaptic membrane (cell body) can produce action potential membrane potential must reach the threshold (we mean the membrane potential of post synaptic membrane).
4. One action potential from one branch of pre-synaptic membrane is not enough to produce action potential in the post synaptic membrane, but we need more than one(in order to reach threshold)
5. Pre-synaptic nerve branches could be excitatory or inhibitory to post synaptic membrane.
· If there is excitation to post synaptic membrane, it is called excitatory post synaptic potential (EPSP).
· If there is inhibition to postsynaptic membrane, it is called inhibitory post synaptic potential (IPSP).
Explanation: if the effect on post synaptic membrane is excitatory, that’s means the membrane potential brought up near to threshold (depolarization toward threshold) but if the effect on post synaptic membrane is inhibitory that’s means the membrane potential is brought down away from the threshold [(hyperpolarization) and it is due to increase permeability to K+ or Cl–, when Cl– enter the cell it increases negativity].
6. If an excitatory potential come, in the same time another inhibitory potential come, what is the result? Is their action potential or not? Answer: each one will abolish other but, if both are excitatory what will happen? Answer; they both depolarize post synaptic membrane, and if the depolarization was enough to reach threshold, then an action potential will result, but, if it is not, then there is only local response in another word we made summation of tow stimuli and the result if depolarize membrane enough to threshold, they will produce action potential.
7. Above mentioned mechanism is called summation and we have two types:
- spatial summation: summation of excitatory postsynaptic potentials (EPSPs) originated simultaneously from several different presynaptic input (from different points in space)
Explanation: when several presynaptic terminals, each one causes EPSP in post synaptic membrane, if the stimuli of these terminals come in same time (simultaneously), there will be adding of one to other until membrane potential reach threshold.
* Spacial = coming from different points in space
B. Temporal summation: summation of several EPSPs occurring very close together in time because of successive firing of a single presynaptic neuron.
· Temporal = the stimuli occur very close in time
Explanation: when single neuron gives rapid, repetitive stimuli (firing) to post synaptic membrane, each stimulus will make change in membrane potential toward threshold, but not enough to reach it, but, because of the stimuli are very close to each other (rapid successive), the effect of second stimulus (which cause EPSP) will be added to first, and the third stimulus will be added to first & second and so on, until reach threshold.
From above we can conclude very important principle which is; we can add graded potentials one to other [i.e. EPSPs], because there is no refractory period for each graded potential (EPSP), and by this we can add second [EPSP] on the top of first [EPSP], and no need to wait first (EPSP) to complete its curve back, because it has no refractory period.
* notice that this fact is not possible in (action potential) because it has refractory period.
Now come back to comparison
Similarities: both synapses and neuro muscular junction have pre synaptic, post synaptic membranes, cleft between them, and pre synaptic release neurotransmitter in response to Ca++ entry and this neurotransmitter bind specific receptor on post synaptic side to change membrane permeability to ions.
1. Synapse is junction between neurons, while neuromuscular junction is junction between motor neuron and muscle fiber (cell).
2. In synapse there might be multiple nerve terminal branches terminate on single cell body, while in neuromuscular junction there is only one nerve terminal for each one muscle fiber (one – to – one transmission).
3. In synapses, the effect of pre synaptic terminals could be excitatory or inhibitory, while in neuromuscular junction there is only excitatory type, and inhibition could be possible outside the junction [e.g. Inhibition of motor neuron (that innervate muscle) in the CNS].
4. Summation in synapses is possible while in neuromuscular junction it is not, but in between muscle fibers during contraction it could be (summation) possible regarding strength of contraction and not (action potential.)
1. One axon (as we mentioned) branch to may terminals and each one (branch) make junction with single muscle fiber so we have single axon that innervate multiples muscle fibers this is called (motor unit).
2. One cell body (of neuron) could have more than 100 nerve terminal attached to it and they could be excitatory or inhibitory or mixed, and the sum of them will judge whether there is action potential or not.
Convergence & divergence:
1. When multiple nerve branches (terminals) terminate on single neuron body. This is called convergence .
2. When single axon branches to multi terminals and each terminal terminate on a different cell body. This is called divergence .
3. They both occur in synapses, but, in neuromuscular junction only divergence occurs [when we have a neuron axon branches, each one terminate on muscle fiber (motor unit)].
Duration of action potentials:
1. Duration of action potential in nerves is about 1 millisecond while in skeletal muscle membrane about 10 millisecond while in cardiac muscle about 200-300 millisecond.
2. as a principle; when duration of action potential increase, the duration of refractory period increase also, and when refractory period increases, then we have less frequent number of action potential produced per minute .
3. Duration of action potential in smooth muscles is largest than all, it is about 1000 m second
1. Duration of action potential in cardiac muscle is longer because after depolarization we have a period of plateau (flatness) caused by influx of Ca++ to inside through slow Ca++ channels.
Explanation: as we know that entrance of positive charge to inside causes depolarization, so when depolarization in cardiac muscle finish and repolarization begin (by K+ efflux), in the same time Ca++ start to enter trying to (depolarize) and (K+) trying to (repolarize) and the result is a period of flatness (plateau) until Ca++ entrance stop and just K+ remain moving outside and by this repolarization is done.
2. Notice that duration of muscle contraction is related to duration of action potential in that muscle, so, we expect that the duration in cardiac muscle contraction is long, and in smooth muscle is longer. (This fact has importance in next lectures).