Signal Transduction in the Brain: Transcript Part 2
Biochemical Pathways in Nerve Cell Function
Protein phosphorylation reactions:
So armed with all of this biochemical inventory, it seemed as though we might go ahead and try to find out whether in fact, these biochemical pathways were important in nerve cell function.
And this slide shows in highly schematic form, a summary of what we now know about synaptic transmission. Here is the presynaptic terminal--nerve impulses coming down to the terminal--that causes a release in neurotransmitter, and here the postsynaptic cell where the neurotransmitter is detected by the receptors producing a physiological response. It is not the topic of my talk this evening but I should mention in passing that these protein phosphorylation reactions are not only very important in the post synaptic membrane--and that will be the main part of my discussion tonight--but they are also very important in these presynaptic terminals.
In a series of studies, we found a family of proteins calls synapsins which are the major phosphoproteins in the brain. And we found out in a series of studies in collaboration with Rodolfo Llinas and Eric Kandel (separate studies with each of them) that the state of phosphorylation of the synapsins determines the efficiency of neurotransmitter release, that is to say, how many molecules, how many vesicles fuse in response to a nerve impulse coming down to the terminal.
Receptor activation by neurotransmitters:
On the postsynaptic side it turned out that these neurotransmitters, by activating the receptors, caused a biochemical cascade which is summarized here. First of all, one or another second messenger was produced--and these could be either cyclic AMP, cyclic GMP, calcium or diisoglycerol These second messengers in turn activated protein kinases. There are various second messenger-dependent protein kinases which are activated by their specific protein kinase second messengers.
The protein kinases then were found by Angus Naim and Ivar Walaas to phosphorylate more than 100 different substrate proteins in the brain. And some of these proteins have very, very interesting, different properties and we have categorized these into four major groups.
Four Major Groups of Substrate Proteins
- Neurotransmitters:
One major group are the receptors for the neurotransmitters themselves, and phosphorylation of these receptors alters their ability to be regulated by neurotransmitters. In other words it sets the "gain" of the system. It determines whether a neurotransmitter molecule will be effective or not in activating a receptor--its state of phosphorylation.
- Sodium and Potassium Channels:
There are also the sodium and potassium channels, which form the basis of the nerve impulse, are regulated by protein phosphorylation.
- Ion Pumps:
The ion pumps, which restore ionic equilibrium, are regulated by protein phosphorylation.
Transcription Factors:
And a variety of transcription factors are regulated by protein phosphorylation of the cell nucleus and thereby control protein synthesis and provide long term storage for information, memories of activity in these nerve cells which has been a subject that Eric Candel has been studying for many years.
Protein Phosphorylation Summary:
So what protein phosphorylation does is to regulate the efficiency of synaptic transmission at fast synapses, both by controlling the amount of neurotransmitter release per nerve impulse and by controlling the efficacy of the neurotransmitter on the post synaptic side. And although this story is now, I think, very well received, it was very controversial for a long time. In some ways it is hard to understand that but on the other hand there are good reasons. It was hard for people to accept the idea that these relatively slow reactions, at least slow chemical reactions involving protein phosphorylation and dephosphorylation, might be involved in something as fast as synaptic transmission which can occur in less than 1000th of a second. That is a more substantial reason. A less substantial reason was that people at the time that we started this work were not very inclined to think that the biochemistry played any role in brain function. Not very long before he died, Sir. John Eccles, a Nobel Laureate, was asked what the role of biochemistry was in the study of the brain and he said, "None." This is kind of amazing and it reflected a lot of the traditional electrophysiologists' attitudes. Probably there were two kinds of people studying brain function. There were the electrophysiologists who, like Sir. John, were not at all interested in what the underlying biochemical mission was. And then there were biochemists who--there were no neuroscientists, there were just people who did electrophysiology of nerve cells--used the brain as a convenient source, a rich source, of enzymes. They would throw a brain into a Waring blender with as much abandon as they would a liver, and these two groups never talked to each other, which is just as well because on the rare occasions they did, they didn't have very nice things to say to each other.
< previous section | next section >
More: Signal Transduction in the Brain
|
