(Transcribed from Dr. Glasser’s lecture, 17 May 2000 by Brian Buschman)
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Axons and only axons fire action potentials (AP) according to what we need to know for the USMLE. The AP is important because an axon membrane is a lousy conductor. The axon must fire the AP to constantly regenerate the signal so that it keeps it’s strength as it propagates.
As AP is a Na+ influx followed by a K+ efflux. Remember that it only takes a very few molecules of ion to move to create the change in membrane potential associated with an AP.
The concentration of Na+ is always about ten times more outside the membrane then it is on the inside so it would not be possible for the Na+ to go back out on it’s own. The repolarization is a function of a K+ efflux. The gradient is maintained by a Na+/K+ pump. This Na+/K+ ATPase can be poisoned by wabbane. If we do this we can see that concentration gradients are large enough to still fire thousands of APs before a significant change in concentration gradient is made.
Digitalis (digitoxin) has a similar effect on cardiac tissue. In cardiac muscle the action is carried out by Ca++ stimulation so digitalis inhibits the Ca++/Na+ pump. It is used clinically to reduce the heart rate of patients.
Tetrodotoxin (TTX) is the chemical which inhibits the Na+ channels by blocking the outer gate. It is found naturally in puffer fish liver and ovaries.
Tetraethylamonium (TEA) is an experimental drug that blocks the K+ channels.
In a neuron the AP moves in myelinated neurons by salutatory conduction. Na+ and K+ channels exist only at the nodes of Ranvier because there is no need for them anywhere else.
PNa+ stands for Na+ permeability and represents the flux that can exist across a given membrane.
GNa+ represents the conductance, which is the amount of actual ionic flow that is possible across the membrane.
For our class purposes we will use the two terms interchangeably and it’s not important to understand the difference.
Increases in PNa+ at the end of the axon will lead to an increase in Pca2+. In an electrical synapse there are gap junctions which will carry the current directly into the next cell. We have them in intercalated disks of myocardial cells but not in nerves.
In our nerves synapses are chemical synapses. In this case the Ca++ influx triggers the release of the neurotransmitter (NT) from the presynaptic terminal. It will diffuse across the synaptic cleft and bind to the post synaptic membrane. Synapses communicate from neuron to neuron and from neuron to effecter tissue (muscle, glands or immune cells).
A neuronal system must include mechanisms for:
The NT never enters the post synaptic cell but rather binds to a receptor on the surface and is then released. If it’s still there it will rebind to stimulate the neuron again.
The nature of the response is a function of the postsynaptic tissue and not of the NT. That is a given NT may be either excitatory or inhibitory depending on the receptor membrane.
1) ACh - Has an effect on cholinergic receptors, is used all over the body and is inactivated by acetlycholine esterase.
2) Catacholamines (NE, Epi, dopamine) – In humans NE is the primary catacholamine NT which Epi is primarily a hormone. They function on adrenergic receptors.
· When sympathetically stimulated the adrenal medulla synthesizes Epi, NE and dopamine but most of the secretions are Epi.
· Dopamine is mostly found in the substancia nigra and the deficiency of dopamine is Parkinson’s disease.
· Catacholamines can be either takes back up by Na+-dependant rapid reuptake or can de degraded by COMT and MAO.
3) Biogenic amines (seratonin, 5-HT) are inactivated by rapid Na+-dependant reuptake.
4) Glycine works at either excitatory or inhibitatory.
5) Asparagine works as either excitatory or inhibitatory.
6) Glutamate is primarily a CNS excitatory NT.
7) GABA is the primary CNS inhibitatory NT.
1) Substance P is mainly used in pain transmission in the dorsal gray of the spinal cord.
2) Enkaphalenes and endorphins are major CNS effectors related to analgesia.
3) CCK can be used as an NT.
4) CRH (corticotrophin releasing hormone) is used as a NT.
Dale’s principle is that all vesicles at an axon’s terminal have one and only one type of NT. This is wrong because a single axon can have up to 27 different large molecule NTs. The debate comes in as to how it selects for release of one over the others.
Myasthenia gravis is a disease resulting from production of an antibody to skeletal muscle ACh receptors. Patients (PTs) present with general weakness that gets worse as the day goes on. It is a progressive disease and eventually if untreated will paralyze the diaphragm. To diaganose it you give the PT tensilin which blocks ACh esterase for a short time. If the PT is energized for a few minutes the test is positive. Normal people will show no effect.
This used to be treated with neostigmine which is a longer active anti-ACh esterase. This just slowed the course of the disease. The modern treatment is to give neostigmine, anti-inflammatory and anti-immune drugs and to perform a thymectomy. This will completely reverse the disease and within a year all the drugs can be removed.
Curie (Indian arrows) is a competitive antagonist for ACh at the neuromuscular junction. If it functions at the level of the diaphragm it will kill you.
Bungarotoxin is like curie in that it competitively inhibits ACh receptors.
Botulism toxin prevents the release of ACh.
Black widow spider venom causes excessive release of ACh. It’s not powerful enough to kill an adult human but can kill small children.
Coca (cocaine) prevents the reuptake of biogenic amines. People die of a MI due to over stimulation.
Axons from between the axon of one neuron and either the soma or a dendrite of another neuron. When the Ca++ influx causes the release of NT the postsynaptic response can be either excitatory or inhibitatory.
1) EPSP (excitatory post synaptic potential). The receptor’s membrane will become depolarized by about 1-3 mV for a period of 3-5 seconds one NT stimulation. THE DEPOLARIZATION IS THE RESULT OF CATION PERMEABILITY. Na+ is one of the cations but it’s not the only one that leads to the EPSE. This is very likely an exam question. This is usually not sufficient to cause an AP because threshold is usually about 15mV above the resting potential.
2) IPSP (inhibitatory post synaptic potential). This is the depolarization resulting from the opening of Cl- channels which allow a Cl- influx which causes hyperpolarization.
As stated one EPSP is not enough of a depolarization to cause an AP. It requires temporal summation. This can be achieved by multiple neurons releasing NT onto one postsynaptic neuron at once or by one increasing it’s NT release. The term ligand gated response implies that if more ligand (NT) is released onto the membrane there will be a greater depolarization which may approach threshold.
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