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Signal Transduction in the Brain: Transcript Part 1
Communication between Nerve Cells
Thank you, George, for your very gracious introduction. As George said, I have had a number of relationships over the years with the MBL and Woods Hole, starting more than half a century ago when I took the embryology course here. It is amazing how little has changed in that more than half of century. There are a few new buildings, but the main thing I have noticed is that a few of my friends look a little older than they did back then.
I am going to talk to you tonight about some of the studies we have been doing on communication between nerve cells in the nervous system. It is estimated, and these estimates are very rough, that there are approximately 100 billion nerve cells in the human brain and that on average, each of these nerve cells has direct contact with about 1,000 other nerve cells.
This first image shows a highly simplified form of communication between two nerve cells across a structure called a synapse. And what happens is that a physiological signal, or nerve impulse, is initiated in these fingerlike projections called dendrites. The signal comes down the dendrite across the cell body, down this elongated process called an axon, to the nerve terminal where it transsynaptically activates this post-synaptic second order target nerve cell. And one of the major debates that raged for about 40 years, from the 1930s to the 1960s, was as to the nature of this intercellular communication between two nerve cells.
There were two schools of thought. The electrical school held that the nerve impulse, since it was manifested as a change in the membrane potential, caused this transsynaptic activation by virtue of changing the electrical field across the plasma membrane of the target nerve cell.
The other school--the chemical school--believed that chemicals called neurotransmitters caused communication between these nerve cells and more specifically, the idea was that as the nerve impulse came down the membrane to the terminal, there was a depolarization, an opening up of voltage-sensitive calcium channels, and calcium then caused diffusion of synaptic vesicles (the brown circles) with the membrane. They released the transmitters, shown here as these blue dots, which then activated what at that time were hypothetical receptors for the neurotransmitters on the plasma membrane of the post synaptic nerve cell.
And this debate was won rather resoundingly by the chemical school, and it is now widely accepted that more than 99% of all synapses are chemical in nature. So at the time that I started this particular aspect of our studies, I was interested in the mechanisms by which the release of neurotransmitter, by combining with these receptors on the post synaptic membrane, produced the physiological response in the target cell.
Fast Synaptic Transmission:
And we know today that there are two major categories of synaptic transmission referred to as fast and slow synaptic transmission. In the case of fast synaptic transmission, Rodolfo Linas showed in pioneering studies he did a very long time ago, that the speed of communication is under 1 millisecond--less than 1/1000 of a second for this process to be completed--of the communication between the presynaptic and the postsynaptic nerve cell.
Excitatory and Inhibitory Fast Synaptic Transmissions:
About half of the fast synapses in the brain are excitatory and the large majority of these fast excitatory synapses use a neurotransmitter called glutamate. The other half of the fast synapses are inhibitory in nature, and these fast inhibitory synapses use a neurotransmitter called GABA. And the reason that they are so fast, we know today, is due to the fact that when the neurotransmitter combines with the receptor there is an opening of a ligand-operated ion channel. I am going to illustrate that for you in the case of glutamate, the excitatory fast transmitter.
Example of fast excitatory synaptic transmission:
So this would be, say, a glutamate molecule. Here is the glutamate receptor in the post synaptic membrane which is in a closed confirmation, but when the glutamate reaches the receptor, it causes a conformational change. The receptor then becomes permeable to sodium ions. Since the sodium ions are positively charged, they cause a depolarization of this membrane, which is excitatory in nature, and contributes to the firing of a nerve impulse.
Example of fast inhibitory synaptic transmission:
The situation with regard to fast inhibitory transmission is very similar except that instead of glutamate you have GABA, and instead of sodium ions you have chloride ions. And since the chloride ions are negatively charged, this means you get a hyperpolarization rather than a depolarization of the membrane, and this is inhibitory in nature.
Slow Synaptic Transmission:
The situation with regard to slow synaptic transmission is incredibly more complex. Virtually every known biogenenic amine and every known peptide neurotransmitter produce their effects on their target cells by these slow synaptic transmission pathways that I am going to describe for you. Even the fast acting neurotransmitters, glutamate and GABA, produce many of their effects through slow synaptic transmission and I am going to tell you a bit about that as well.
Prior Studies on Synaptic Transmission- Sutherland and Krebs:
So our work on slow synaptic transmission was inspired by studies that were carried out by Earl Sutherland and Edwin Krebs who had been studying the mechanism by which the hormones epinephrine and glucagon break down glycogen in liver. What Sutherland found was that epinephrine and glucagon cause the activation of an enzyme which he called adenyl cyclase and this caused the conversion of ATP to cyclic AMP. Sutherland then went on to show that the cyclic AMP could mimic the hormones, causing the breakdown of the glycogen. So he showed that the hormone made cyclic AMP and that the cyclic AMP mimicked the hormone in breaking down glycogen.
Protein Kinases:
Edwin Krebs then showed that the way the cyclic AMP broke down the glycogen was to activate an enzyme which he called a cyclic AMP-dependent protein kinase which is the more general category of protein kinase. Protein kinases are enzymes which transfer phospate from adenosine triphosphate (ATP) to substrate proteins with the formation of adenosine diphosphate (ADP) and the phosphorylated substrate protein. Krebs and his colleagues then showed that the substrate protein was an enzyme known as phosphorylase kinase which in turn catalyzed the breakdown of the glycogen.
So between the work of Sutherland and Krebs we knew that these hormones caused the formation of a cyclic AMP which activated a protein kinase which activated a substrate protein which broke down glycogen. And the possibility occurred to me that this might be how nerve cells communicate with each other. There was a major reason for thinking that this idea was probably wrong which was that hormones work over very large distances, up to meters in distance between the cell releases the hormone and the target cell the response to the hormone. In contrast, in synapses the distance is about one, one-millionth of a centimeter. So there are very different scales that we are looking at. Nevertheless, we decided to go after this.
I forgot an important point. This protein kinase reaction is reversed by an enzyme called a protein phophatase which removes phosphate from the substrate protein and returns the system to its original state, with the generation of inorganic phosphate.
Studies of Enzymes Activated by Neurotransmitters:
So I started to say that we began to look to see whether we could find adenyl cyclases that were activated by neurotransmitters in the nervous system, and we found a family of them including, most interestingly, the dopamine-sensitive and the serotonin-sensitive adenyl cyclase. The first such enzyme we found was dopamine-sensitive adenyl cyclase. This was work of John Kebabian. And we obtained evidence that I won't go into, for its possible role in synaptic transmission. This is in 1971.
About a year earlier, Miyamoto and Kuo were able to find a cyclic AMP-dependent protein kinase in mammalian brain with the same properties that had been found by Krebs in his studies of liver. Even more interesting was the fact that the concentration in brain of this enzyme was enormously higher than in the liver. And still more interestingly, the enzyme was located at the synaptic region of nerve cells, so we were encouraged by these biochemical studies to think we might be on the right track.
We then found some other second messenger-dependent protein kinases about the same time we found a protein kinase which got activated by cyclic GMP rather than cyclic AMP. Cyclic GMP is a short term for guanosine monophosphate and this enzyme we found to be present not only in the brain, but present in peripheral tissues as well.
And a few years later, we were able to find a protein kinase that was stimulated by calcium in the presence of an endogenous heat stable protein which later on turned out to be this newly discovered molecule, calmodulin, which in the presence of calcium activates various enzymes.
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