Neurotransmitters

In the first part of the XXth century, it was clear that electric impulses were an important component in the signaling of the nervous system.

This clarified some aspects of signaling in the nervous system, but at the same time, more questions arised: Why is the nervous impulse generated in the first place? Which is the initial stimuli that starts the electric signalization?

Before 1950, when the electronic microscope was created, the Cajal vs. Golgi debate was open two discussion.

There were two irreconcilable theories, one that preached that chemical substances were the responsible in the transmission of the signal from one neuron to another, because they were mediators in a existing gap between neurons.

And another group, that considered that there was not such a gap, and the electric signal was continuous. This last group thought that a mediator (the chemical substance) would slow down the process so much, that it would be impossible for the nervous system to act as fast as it did.  For them, the patellar reflex was an evidence of their explanation.

The supporters of the neuronal theory, started the pursuit of a mediator between neurons. The substance that, hypothetically,, crossed the gap between cells.

In 1921, the pharmacologist Otto Loewi, appeared in the scene. It was known that adrenaline, the chemical substance associated with the kidney, sped up the beat of the heart and that involuntary corporal processes, like this one, were dependent on the autonomous nervous system. There was no proof, though, that adrenaline functioned as a direct chemical mediator between the nerve and the heart, because there was another option, another step that controlled the heart of the beat and was unknown. In addition, communication between the autonomous nervous system and the heart was hypothesized to be of electric nature.

One vivid dream, gave Otto Loewi a clear idea on how to perform an experiment to demonstrate his suspicion on how the conexion between the speeding of the heart and the ANS, was mediated by adrenaline.

Fig 1. Otto Loewi’s experiment
(From: edumed.org.br)

He used two hearts, one of them was still attached to the vagus nerve, the other one wasn’t.
It was known that the electrical stimulation of the vagus nerve slowed down the heartbeat, so he outlined: If a chemical signal was released by the vagus nerve when stimulated, it should dilute in the saline solution where he kept the heart-nerve preparation. If he extracted this solution and pour it into another preparation the same thing should happen: the heartbeat should slow down.

When he stimulated the vagus nerve, collected the substance, and pour it into the preparation that lacked the vagus nerve, the liquid slowed down the heartbeat in that preparation.

The extrapolation, was obvious, the effect happened because of the diluted chemical.   
Loewi assumed, that the solution contained what he called “vagus material” (Vagusstoff), a type of chemical messenger. This was later identified as the neurotransmitter acetylcholine.

In 1936, he received the first Nobel prize for the discovery of a neurotransmitter and its signalization mechanism. After this event, a lot of other scientists followed, and discovered a lot more neurotransmitters.

Otto Loewi shared the Nobel Prize with his dear friend, Henry Dale. Dale layed out the chemical neurotransmission in the neuromuscular unions. The conexion that happens between a motor neuron and a muscular neuron and is involved in the control of voluntary movements.

Other Nobel Prizes regarding neurotransmission:

  • Julius Axelrod / Ulf von Euler/Bernard Katz. 1970. “For their discoveries concerning the humoral transmittors in the nerve terminals and the mechanism for their storage, release and inactivation.”

Julius Axelrod studied noradrenaline in extension. He explained how this signal substance is involved in the regulation of activity in situations of danger or aggression. In addition, he showed how in response to electric stimuli, and excess of noradrenaline is released and later restored, once the signal is transmitted.

Ulf von Euler discovered in collaboration with John H. Gaddum, the autacoid, substance P. He also discovered prostaglandin and vesiglandin (1935), piperidine (1942) and noradrenaline (1946).

Bernard Katz demonstrated how acetylcholine, a signal substance, is released in certain amounts in synapses. 

  • Roger Guillemi/Andrew V.Schally. 1977. “For their discoveries concerning the peptide hormone production of the brain.”

Roger Guillemi and Andrew V. Schally, working separatedly, were able to extract, and therefore, study the structure of Gonadotropin-releasing hormone (GnRH) and Thyrotropin-releasing hormone (TRH). They could isolate somatostatin (GHIH) and endorphins as well.

  • Arvid Carlsson/Paul Greengard. 2000.”For their discoveries concerning signal transduction in the nervous system.”  

Arvid Carlsson discovered and described important aspects of the chemical signal, Dopamine, focusing specially in its role in our ability to move.

Paul Greengard focused on how neurotransmitters like dopamine, 5HT and noradrenaline, activated second messenger cascades trough its interaction with receptors in the cell membrane.

  • Thomas Südhof/James E. Rothman/Randy W. Schekman. 2013. “For their discoveries of machinery regulating vesicle traffic, a major transport system in our cells.”

Thomas Sudhof demonstrated how vesicles are held in its place, and how they react in response to specific signals to release its contents into the synapses.

James E. Rothman collaborated to the understanding of vesicular trafficking in his studies of how key proteins binds in specific combinations, making possible the precise location of the release of neurotransmitter. He discovered NSF, SNAP proteins and the SNARE complex.

Randy W. Schekman demonstrated that malfunctions in the transportation system of vesicles are due to genetic defects. He also explained how different genes regulate differents aspects of this system.

References

 

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