Nobel Prize in Physiology or Medicine 2000: Signal Transduction in the Nervous System

This note covers the Nobel Prize in Physiology or Medicine 2000, awarded to Arvid Carlsson, Paul Greengard and Eric Kandel: who they were, how nerve cells talk to each other through chemical signals at synapses, how dopamine, protein phosphorylation and memory formation were discovered, how the work unfolded across four decades, why it matters for diseases such as Parkinson's disease, and quick facts for exams.

What was the Nobel Prize in Physiology or Medicine 2000 awarded for?

The official citation reads: "for their discoveries concerning signal transduction in the nervous system". In plain words, the three laureates explained how one nerve cell passes a chemical message to the next nerve cell, and how that message changes what the receiving cell does.

A human brain contains more than a hundred billion nerve cells (neurons), and a single nerve cell can make thousands of contact points, called synapses, with other nerve cells.

The committee's work describes signal transduction as the process by which a chemical released at a synapse is turned into a change inside the receiving cell.

This prize is formally called the Nobel Prize in Physiology or Medicine, and it was announced on 9 October 2000.

The three laureates worked on different pieces of the same puzzle: Carlsson found a key chemical messenger, Greengard found the molecular switch it operates, and Kandel showed how repeated use of that switch builds memory.

The Nobel Assembly at Karolinska Institutet, which decides this prize, said the discoveries had been "crucial for an understanding of the normal function of the brain" and had led to new drugs.

Who are the laureates?

All three laureates shared the prize equally, each receiving one third of the 9,000,000 Swedish kronor award, for discoveries that together explain how nerve cells signal to one another.

Arvid Carlsson

Arvid Carlsson was born on 25 January 1923 in Uppsala, Sweden, and died on 29 June 2018 in Gothenburg, Sweden.

At the time of the award he was affiliated with Göteborg University (the University of Gothenburg) in Gothenburg, Sweden, where he had been a professor of pharmacology since 1959.

He was raised in Lund, where his father was a professor of history at the university, and he went on to study medicine and pharmacology there.

Carlsson's contribution was to show that dopamine is a chemical transmitter in its own right in the brain, not merely a building block for another transmitter, and that it controls movement.

Paul Greengard

Paul Greengard was born on 11 December 1925 in New York, USA, and died on 13 April 2019 in New York, USA.

At the time of the award he worked at the Laboratory of Molecular and Cellular Science, Rockefeller University, in New York.

His contribution was to work out the step-by-step chemical mechanism, called protein phosphorylation, by which dopamine and similar transmitters change the behaviour of a nerve cell after they bind to it.

Eric Kandel

Eric R. Kandel was born on 7 November 1929 in Vienna, Austria. His family fled to New York in 1939 to get away from Nazi rule.

At the time of the award he was affiliated with the Center for Neurobiology and Behavior, Columbia University, New York, where he had been a professor since 1974.

Kandel's contribution was to show, using a sea slug, how changes at the synapse underlie learning and memory, and how short-term memory differs from long-term memory at the molecular level.

What problem were the laureates trying to solve?

By the middle of the twentieth century, scientists knew that nerve cells send electrical impulses along their fibres, but the question of how one nerve cell influences the next one, across the tiny gap of a synapse, was far less clear.

The brain's message system had to rely on chemistry rather than a direct electrical wire, because one cell does not touch the next cell directly at most synapses.

A message from one nerve cell to another is carried by chemical transmitters released into the synapse.

The press release notes that the three laureates' work concerned one particular kind of signalling, called slow synaptic transmission, in which the effect on the receiving cell can last from seconds to hours, unlike the much faster chemical signals used for immediate actions such as movement and sensation.

Before these discoveries, scientists did not understand which chemicals acted as transmitters in the brain, how a transmitter's chemical message was converted into a lasting change inside a cell, or how such changes could add up over time to form a memory.

Disturbances in this signalling were also linked, loosely, to diseases such as Parkinson's disease and schizophrenia, but the underlying mechanism was missing.

Solving these three linked questions, a missing transmitter, a missing mechanism and a missing link to memory, is what the 2000 prize rewarded.

How did Arvid Carlsson identify dopamine and open the door to a Parkinson's disease treatment?

In the late 1950s, Carlsson ran a series of experiments showing that dopamine, previously thought to be only a stepping stone towards another transmitter called noradrenaline, was in fact a transmitter in its own right.

He developed a highly sensitive method to measure dopamine levels in brain tissue and found that dopamine was concentrated in different brain regions from noradrenaline, especially in an area called the basal ganglia, which helps control movement.

Carlsson then used a substance called reserpine, which empties synapses of their stored transmitters, and showed step by step how dopamine relates to movement.

1. Animals given reserpine lost their ability to make spontaneous movements, because their dopamine stores were emptied.
2. Carlsson treated these animals with L-dopa, a chemical the body converts into dopamine, while a separate comparison group received a precursor of serotonin instead.
3. The animals that received L-dopa recovered their normal movement, while a precursor of serotonin did not help.
4. Carlsson confirmed that L-dopa treatment had restored normal dopamine levels in the brain.
5. He connected these findings to Parkinson's disease, reasoning that patients with the disease must have abnormally low dopamine in the basal ganglia.

This reasoning led to L-dopa being developed as a drug for Parkinson's disease, a treatment that the press release describes as "today still is the most important treatment for the disease".

In Parkinson's disease, the brain's dopamine-making nerve cells in the basal ganglia die off, producing tremor, muscle stiffness and difficulty starting movement; L-dopa makes up for the missing dopamine.

Carlsson's later work also showed that antipsychotic drugs used for schizophrenia work by blocking dopamine receptors, and he contributed to developing selective serotonin uptake blockers, a newer class of antidepressant drugs.

Draw a simplified brain outline with the basal ganglia marked, and nerve fibres running from dopamine-producing cells into this region; show these fibres intact in a healthy brain and degenerating in a brain with Parkinson's disease, with a note that this loss causes tremor, rigidity and reduced movement.

How did Paul Greengard work out the mechanism of slow synaptic transmission?

By the late 1960s, scientists already knew that dopamine, noradrenaline and serotonin acted as transmitters in the brain, but not how they produced their effects once released. Greengard's contribution was to uncover the chemical chain of events inside the receiving nerve cell.

He showed that a transmitter binding to a receptor on the cell surface sets off a chain reaction involving a chemical messenger called cyclic AMP, which in turn activates an enzyme called Protein Kinase A.

This enzyme adds phosphate groups to other proteins, a process called phosphorylation, and this changes the shape and function of those proteins. The process can be set out as a sequence of steps.

1. A transmitter, such as dopamine, binds to a receptor on the surface of the receiving nerve cell.
2. This raises the level of the second messenger cyclic AMP inside the cell.
3. Cyclic AMP activates Protein Kinase A, an enzyme that adds phosphate groups to target proteins.
4. Phosphorylation changes the shape of proteins that form ion channels in the cell membrane, altering how easily the cell can fire an electrical impulse.
5. A regulatory protein called DARPP-32 can be switched on by this same route, and it then influences many other proteins at once, much like a conductor directing an orchestra.

This matters because ion channels control a nerve cell's excitability, that is, how readily it fires an impulse. By phosphorylating ion-channel proteins, a transmitter such as dopamine can make a nerve cell more or less likely to respond.

Greengard's discoveries, the sources note, have deepened understanding of how several drugs that affect protein phosphorylation work inside nerve cells.

Draw one nerve cell releasing a transmitter into the synaptic gap, a receptor on the next cell's membrane, an arrow from the receptor to a rising cyclic AMP level inside the cell, an arrow from cyclic AMP to an activated Protein Kinase A, and arrows from the kinase to phosphate groups being attached to an ion-channel protein in the membrane.

How did Eric Kandel use a sea slug to discover how memories form?

Kandel wanted to understand how memories are stored at the level of nerve cells, but a mammalian brain with billions of neurons was too complicated to study directly.

He therefore chose a simpler model, the marine snail Aplysia (a sea slug), which has only around 20,000 nerve cells, many unusually large, and a simple reflex that withdraws its gill when touched.

Kandel found that certain stimuli strengthened this protective reflex, and that the strengthened reflex could last for days or weeks, which counts as a form of learning.

He traced this strengthening to changes at the synapse connecting sensory nerve cells to the nerve cells that drive the muscles of the reflex.

Kandel went on, during the 1990s, to show that the same kind of long-term change in synaptic function seen in the sea slug also occurs in mice, which suggested that the mechanism applies more widely, including to humans.

The sources state that this work provided "a critical building stone" for understanding complex memory, while noting that a full understanding of complex memory in humans was still some way off.

Draw a simple sea slug with a labelled gill, a sensory nerve cell leading from the body surface to a motor nerve cell that controls gill withdrawal, and the synapse between them; mark this synapse as the site where repeated touch produces either a weaker short-term change or, with stronger stimulation, a lasting change in shape linked to long-term memory.

How did the discovery unfold?

Taken together, this timeline shows three separate research lines, started decades apart, that converged on one shared idea: nerve cells change the strength of their synapses using chemical signalling, and this change underlies both the body's control of movement and the brain's ability to remember.

Why does this discovery matter?

The clearest practical result is the drug L-dopa for Parkinson's disease, which the sources describe as enabling patients to live more normal lives by replacing the dopamine their brains can no longer make enough of.

Carlsson's work on dopamine receptors also explained how existing antipsychotic drugs work, and contributed to the development of newer antidepressant drugs that act on serotonin.

Greengard's discovery of the phosphorylation mechanism gave scientists a general explanation for how many different transmitters, not only dopamine, can change a nerve cell's behaviour, which has helped explain the action of drugs that affect mood, alertness and the brain's response to addictive substances such as cocaine, amphetamine and heroin, as noted in the presentation speech.

Kandel's work on the sea slug showed that memory is not a mysterious, separate process but is built from the same kind of synaptic change studied by Carlsson and Greengard.

The sources suggest this understanding could eventually help in developing medication to improve memory in patients with dementia, while being careful to note that a full understanding of how the brain stores complex memories was still an open question at the time of the award.

How does this connect to what you study?

This prize connects directly to the biology topics of the nervous system, neurons and synapses that describe how signals travel through the body.

The idea of a chemical transmitter crossing a synaptic gap, and of a receptor triggering changes inside a cell, is the same basic picture used when school biology explains how nerve impulses are passed from one neuron to the next.

It also links to the study of diseases of the nervous system, since Parkinson's disease is explained here as resulting from the loss of dopamine-producing cells, giving a concrete example of how understanding a chemical mechanism in the body can lead directly to a working medicine.

Students studying cell signalling, enzymes or feedback mechanisms will recognise phosphorylation as one everyday example of how a cell's proteins are switched on and off chemically.

Quick facts for exams

The Nobel Prize in Physiology or Medicine 2000 was awarded jointly to Arvid Carlsson, Paul Greengard and Eric R. Kandel for their discoveries concerning signal transduction in the nervous system.

It was announced by the Nobel Assembly at Karolinska Institutet on 9 October 2000. Each laureate received one third of the prize, worth 9,000,000 Swedish kronor in total.

Carlsson, based at Göteborg University in Sweden, showed dopamine is a brain transmitter linked to movement and Parkinson's disease. Greengard, at Rockefeller University in the USA, showed how transmitters change nerve cells through protein phosphorylation.

Kandel, at Columbia University in the USA, used a sea slug to show how synaptic change underlies short-term and long-term memory.

Note: Source. The prize facts in this note are from the Nobel Prize's official site, nobelprize.org.

Glossary

• Nerve cell (neuron) — a cell specialised to carry electrical and chemical signals through the body's nervous system.
• Synapse — a point of contact between two nerve cells where a chemical signal passes from one cell to the other.
• Signal transduction — the process by which a chemical signal received by a cell is converted into a change inside that cell.
• Transmitter — a chemical released by one nerve cell at a synapse that influences the next nerve cell.
• Dopamine — a transmitter important for control of movement; its loss causes the symptoms of Parkinson's disease.
• L-dopa — a chemical that the body converts into dopamine, used as a drug to treat Parkinson's disease.
• Basal ganglia — brain regions, rich in dopamine, important for controlling movement.
• Slow synaptic transmission — a type of signalling whose effect on a nerve cell can last from seconds to hours.
• Phosphorylation — the chemical addition of a phosphate group to a protein, changing its shape and function.
• Protein Kinase A — an enzyme, activated by cyclic AMP, that adds phosphate groups to other proteins.
• DARPP-32 — a regulatory protein that, once activated, influences the activity of several other proteins in a nerve cell.
• Ion channel — a protein in a cell membrane that controls the flow of ions and so the cell's electrical excitability.
• Aplysia — a marine snail (sea slug) with a simple nervous system, used by Eric Kandel to study memory.
• Short-term memory — a memory lasting minutes to hours, formed without the need for new protein synthesis.
• Long-term memory — a memory that can last weeks, requiring new protein synthesis and a change in synaptic shape.

Common errors and misconceptions

• Misconception: Dopamine was always known to be an important brain transmitter. Correct: Before Carlsson's work, dopamine was believed to be only a stepping stone towards another transmitter, noradrenaline.
• Misconception: L-dopa cures Parkinson's disease. Correct: The sources describe L-dopa as a treatment that restores dopamine levels and normalises movement, not a cure for the underlying loss of dopamine-producing cells.
• Misconception: Phosphorylation and dephosphorylation are the same process. Correct: Phosphorylation adds phosphate groups to a protein; dephosphorylation removes them; both change the protein's shape and function.
• Misconception: Fast and slow synaptic transmission are the same thing. Correct: Slow synaptic transmission produces effects lasting seconds to hours and can influence mood and alertness, while fast transmission underlies immediate actions such as movement and sensation.
• Misconception: Short-term and long-term memory use identical mechanisms. Correct: In the sea slug, short-term memory involves phosphorylation of existing ion-channel proteins, while long-term memory needs the synthesis of new proteins.
• Misconception: Kandel studied human memory directly from the start. Correct: He first used the simpler nervous system of the sea slug Aplysia, and only later extended findings to mice.
• Misconception: All three laureates worked together on one shared experiment. Correct: Each worked largely independently, on dopamine, on phosphorylation mechanisms, and on memory in the sea slug, and the prize recognised how their separate findings fit together.

Exam-style questions with model answers

Q1. For what discovery was the Nobel Prize in Physiology or Medicine 2000 awarded? [2 marks]

1. It was awarded for discoveries concerning signal transduction in the nervous system, that is, how nerve cells pass chemical signals to each other at synapses.

Q2. Name the three laureates of the Nobel Prize in Physiology or Medicine 2000 and their affiliations at the time of the award. [2 marks]

1. Arvid Carlsson at Göteborg University, Paul Greengard at Rockefeller University, and Eric R. Kandel at Columbia University.

Q3. Explain how Arvid Carlsson's experiments with reserpine and L-dopa led to a treatment for Parkinson's disease. [4 marks]

1. Carlsson gave animals reserpine, a substance that empties synapses of stored transmitters, and the animals lost the ability to make spontaneous movements.
2. He then treated the animals with L-dopa, a precursor the body converts into dopamine, and the animals regained normal movement, while a serotonin precursor did not help.
3. He confirmed that L-dopa restored normal brain dopamine levels, showing that the lost movement was due specifically to lost dopamine.
4. Since Parkinson's disease produces similar symptoms, he concluded that patients with the disease had abnormally low dopamine in the basal ganglia, which led to L-dopa being developed as a treatment that still remains the most important drug for the disease.

Q4. Describe the chain of events by which a transmitter such as dopamine changes the behaviour of a nerve cell, according to Paul Greengard's work. [4 marks]

1. The transmitter binds to a receptor on the surface of the receiving nerve cell.
2. This raises the level of the second messenger cyclic AMP inside the cell.
3. Cyclic AMP activates the enzyme Protein Kinase A.
4. Protein Kinase A adds phosphate groups to target proteins, including ion channels, changing their shape and the cell's electrical excitability; the regulatory protein DARPP-32 can also be switched on through this route and in turn influences many other proteins.

Q5. Discuss how Eric Kandel used the sea slug Aplysia to explain the difference between short-term and long-term memory, and why this work was significant. [6 marks]

1. Kandel chose Aplysia because its nervous system has only around 20,000 nerve cells and a simple protective reflex that withdraws its gill, which made it possible to study learning without the complexity of a mammalian brain.
2. He found that certain stimuli strengthened this reflex for days or weeks, which counted as a form of learning, and traced the change to the synapse between the sensory nerve cell and the motor nerve cell controlling the reflex.
3. Weaker stimuli produced a short-term memory lasting minutes to hours, caused by phosphorylation of ion-channel proteins that increased calcium entry and transmitter release at the existing synapse.
4. Stronger, repeated stimuli produced a long-term memory lasting weeks, caused by raised cyclic AMP and Protein Kinase A activity reaching the cell nucleus, triggering new protein synthesis and a change in the shape of the synapse; blocking new protein synthesis blocked long-term memory but not short-term memory.
5. During the 1990s, Kandel showed the same type of long-term synaptic change also occurs in mice, suggesting the mechanism is shared more widely, which the sources describe as a critical building block for understanding memory and, potentially, for future treatments for memory disorders such as dementia.

Q6. What is slow synaptic transmission, and why is it described as important for understanding both normal brain function and disease? [3 marks]

1. Slow synaptic transmission is a type of chemical signalling at synapses whose effect on the receiving nerve cell can last from seconds to hours, rather than producing an immediate, brief response.
2. It is involved in basic brain functions such as alertness and mood, and it can also control faster synaptic transmission used for movement, speech and sensory perception.
3. Disturbances in this slow signalling, as shown by the three laureates' work, are linked to neurological and psychiatric diseases such as Parkinson's disease, and understanding the mechanism has led to the development of new drugs.

Key takeaways

• The Nobel Prize in Physiology or Medicine 2000 went to Carlsson, Greengard and Kandel for signal transduction in the nervous system.
• Arvid Carlsson showed that dopamine is a transmitter controlling movement, leading to L-dopa for Parkinson's disease.
• Paul Greengard showed that transmitters act through cyclic AMP, Protein Kinase A and protein phosphorylation.
• DARPP-32 acts like a conductor, letting one signal influence many proteins in a nerve cell at once.
• Eric Kandel used the sea slug Aplysia to show how synapses change during learning and memory.
• Short-term memory needs only existing protein changes, while long-term memory needs new protein synthesis.
• Carlsson's dopamine work also explained how antipsychotic drugs and some antidepressants act in the brain.
• The prize was announced on 9 October 2000 and shared equally among the three laureates.

Test yourself

What did the official citation for the Nobel Prize in Physiology or Medicine 2000 say?

It said the prize was "for their discoveries concerning signal transduction in the nervous system", referring to how nerve cells chemically signal each other.

Where was Arvid Carlsson based when he received the Nobel Prize?

Arvid Carlsson was affiliated with Göteborg University in Gothenburg, Sweden, at the time of the award.

What substance did Carlsson use to empty nerve cells of their transmitters, and what happened to the animals?

He used reserpine, which depleted transmitter stores, and the treated animals lost their ability to make spontaneous movements.

What second messenger did Greengard show is raised when dopamine binds its receptor?

Paul Greengard showed that dopamine binding its receptor raises the level of the second messenger cyclic AMP inside the nerve cell.

What is DARPP-32 and what does it do?

DARPP-32 is a regulatory protein that, once activated, influences many other proteins, acting like a conductor directing their activity in the nerve cell.

Why did Eric Kandel choose to study the sea slug Aplysia rather than a mammal?

Aplysia has a simple nervous system of only around 20,000 nerve cells and a simple reflex, making it easier to trace memory to specific synapses.

What is the key difference between short-term and long-term memory in Kandel's experiments?

Short-term memory needs no new proteins, while long-term memory requires new protein synthesis and a lasting change in the synapse's shape.

How much prize money was awarded for the Nobel Prize in Physiology or Medicine 2000, and how was it shared?

The prize was 9,000,000 Swedish kronor, shared equally, one third each, among Carlsson, Greengard and Kandel.