2003年两位研究细胞膜的美国科学家获诺贝尔化学奖2003

HUSTRen 发表于 2003/10/08 15:49 华中科技大学校友论坛 (www.hust.org)

加跟贴 发新贴

The Nobel Prize in Chemistry 2003 � Information for the Public

8 October 2003

All living matter is made up of cells. A single human being has as many as the stars in a galaxy, about one hundred thousand

million. The various cells � e.g. muscle cells, kidney cells and nerve cells � act together in an intricate system in each one of us.

Through pioneering discoveries concerning the water and ion channels of cells, this year誷 Nobel Laureates Peter Agre and

Roderick MacKinnon, have contributed to fundamental chemical knowledge on how cells function. They have opened our

eyes to a fantastic family of molecular machines: channels, gates and valves all of which are needed for the cell to function.

Molecular channels through the cell wall

To maintain even pressure in the cells it is important that water can pass through the cell wall. This has been known for a long

time. The appearance and function of these pores, remained for a long time as one of the classical unsolved problems of

biochemistry. It was not until around 1990 that Peter Agre discovered the first water channel. Like so much else in the living

cell, it was all about a protein.

Water molecules are not the only entities that pass into and out of the cell. For thousands of millions of cells to be able to

function as something other than one large lump, coordination is required. Thus communication between the cells is necessary.

The signals sent in and between cells consist of ions or small molecules. These start cascades of chemical reactions that cause

our muscles to tense, our eyes to water � indeed, that control all our bodily functions. The signals in our brains also involve

such chemical reactions. When we stub a toe this starts a signal moving up towards the brain. Along a chain of nerve cells,

through interaction between chemical signals and ion currents, information is conveyed from cell to cell like a baton in a relay

race.

It was in 1998 that Roderick MacKinnon succeeded for the first time in showing what ion channels look like at atomic level �

an achievement which, together with Agre誷 discovery of water channels, opened up entirely new research areas in

biochemistry and biology.

The medical consequences of Agre誷 and MacKinnon誷 discoveries are also important. A number of diseases can be attributed

to poor functioning in the water and ion channels of the human body. With the help of fundamental knowledge of what they

look like and how they work, there are now new possibilities for developing new and more effective pharmaceuticals.

High resolution image (jpeg 210 kB) �

Fig 1. The dividing wall between the cell and the outside world � including other cells � is far from being an

impervious shell. On the contrary, it is perforated by various channels. Many of these are specially adapted to one

specific ion or molecule and do not permit any other type to pass. Here to the left we see a water channel and to the

right an ion channel.

Water channels

The hunt for the water channels

As early as the middle of the nineteenth century it was understood that there must be openings in the cell membrane to permit

a flow of water and salts. In the middle of the 1950s it was discovered that water can be rapidly transported into and out of cells

through pores that admit water molecules only. During the next 30 years this was studied in detail and the conclusion was that

there must be some type of selective filter that prevents ions from passing through the membrane while water molecules, which

are uncharged, flow freely. Thousands of millions of water molecules per second pass through one single channel!

Although this was known, it was not until 1992 that anybody was able to identify what this molecular machinery really looked

like; that is, to identify what protein or proteins formed the actual channel. In the mid-1980s Peter Agre studied various

membrane proteins from the red blood cells. He also found one of these in the kidney. Having determined both its peptide

sequence and the corresponding DNA sequence, he realised that this must be the protein that so many had sought before him:

the cellular water channel.

Agre tested his hypothesis in a simple experiment (fig. 2) where he compared cells which contained the protein in question

with cells which did not have it. When the cells were placed in a water solution, those that had the protein in their membranes

absorbed water by osmosis and swelled up while those that lacked the protein were not affected at all. Agre also ran trials with

artificial cells, termed liposomes, which are a type of soap bubble surrounded on the outside and the inside by water. He found

that the liposomes became permeable to water if the protein was planted in their membranes.

What is osmosis?

The liquid pressure in plant and animal cells is maintained through osmosis. In osmosis, small

molecules (such as water) pass through a semi-permeable membrane. If the membrane does not

admit macromolecules or salts that are in higher concentrations on one side of the membrane, the

small molecules (water) will cross to this side, attempting to 觗ilute� the substance that cannot

pass through the membrane. The osmotic pressure thus arising is the reason why cells are often

swollen and stiff, in a flower stalk, for example.

High resolution image (jpeg 165 kB) �

Fig 2. Peter Agre誷 experiment with cells containing or lacking aquaporin. The aquaporin is necessary for making

the cell absorb water and swell.

Peter Agre also knew that mercury ions prevent cells from taking up and releasing water, and he showed that water transport

through his new protein was prevented in the same way by mercury. This made him even more sure of that he had discovered

what was actually the water channel . Agre named the protein aquaporin, 觲ater pore�.

How does the water channel work? A question of form and function

In 2000, together with other research teams, Agre reported the first high-resolution images of the three-dimensional structure

of the aquaporin. With these data, it was possible to map in detail how a water channel functions. How is it that it only admits

water molecules and not other molecules or ions? The membrane is, for instance, not allowed to leak protons. This is crucial

because the difference in proton concentration between the inside and the outside of the cell is the basis of the cellular

energy-storage system.

Selectivity is a central property of the channel. Water molecules worm their way through the narrow channel by orienting

themselves in the local electrical field formed by the atoms of the channel wall. Protons (or rather oxonium ions, H3O+) are

stopped on the way and rejected because of their positive charges.

High resolution image (jpeg 173 kB) �

Animations �

Fig 3. Passage of water molecules through the aquaporin AQP1. Because

of the positive charge at the center of the channel, positively charged ions

such as H3O+, are deflected. This prevents proton leakage through the

channel.

The medical significance of the water channels

During the past ten years, water channels have developed into a highly topical research field. The aquaporins have proved to be

a large protein family. They exist in bacteria, plants and animals. In the human body alone, at least eleven different variants

have been found.

The function of these proteins has now been mapped in bacteria and in plants and animals, with focus on their physiological

role. In humans, the water channels play an important role in, among other organs, the kidneys.

The kidney is an ingenious apparatus for removing substances the body wishes to dispose of. In its windings (termed

glomeruli), which function as a sieve, water, ions and other small molecules leave the blood as 詐rimary� urine. Over 24 hours,

about 170 litres of primary urine is produced. Most of this is reabsorbed with a series of cunning mechanisms so that finally

about one litre of urine a day leaves the body.

From the glomeruli, primary urine is passed on through a winding tube where about 70% of the water is reabsorbed to the

blood by the aquaporin AQP1. At the end of the tube, another 10% of water is reabsorbed with a similar aquaporin, AQP2.

Apart from this, sodium, potassium and chloride ions are also reabsorbed into the blood. Antidiuretic hormone (vasopressin)

stimulates the transport of AQP2 to cell membranes in the tube walls and hence increases the water resorption from the urine.

People with a deficiency of this hormone might be affected by the disease diabetes insipidus with a daily urine output of

10-15 litres.

Ion channels

The cells signal with salt!

The first physical chemist, the German Wilhelm Ostwald (Nobel Prize in Chemistry 1909) proposed in 1890 that the electrical

signals measured in living tissue could be caused by ions moving in and out through cell membranes. This electro-chemical

idea rapidly achieved acceptance. The notion of the existence of some type of narrow ion channel arose in the 1920s. The two

British scientists Alan Hodgkin and Andrew Huxley made a major breakthrough at the beginning of the 1950s and for this

were awarded the Nobel Prize in Physiology or Medicine in 1963. They showed how ion transport through nerve cell

membranes produces a signal that is conveyed from nerve cell to nerve cell like a relay race baton. It is primarily sodium and

potassium ions, Na+ and K+, that are active in these reactions.

Thus as much as fifty years ago there was well-developed knowledge of the central functions of the ion channels. They had to

be able to admit one ion type selectively, but not another. Likewise, it had to be possible for the channels to open and shut and

sometimes to conduct ions in one direction only. But how this molecular machinery really worked was long to remain a

mystery.

Ion-selective channel

During the 1970s it was shown that the ion channels were able to admit only certain ions because they were equipped with

some kind of 觟on filter�. Of particular interest was the finding of channels that admit potassium ions but not sodium ions �

even though the sodium ion is smaller than the potassium ion. It was suspected that the oxygen atoms in the protein played an

important role as 襰ubstitutes� for the water molecules with which the potassium ion surrounds itself in the water solution and

from which it must free itself during entry to the channel.

But further progress with this hypothesis was difficult � what was now needed was simply high-resolution pictures of the type

only X-ray crystallography can provide. The problem was that it is extremely difficult to determine the structure of membrane

proteins with this method, and the ion channels were no exception. Membrane proteins from plants and animals are more

complicated and difficult to work with than those from bacteria. Using bacterial channel proteins that resemble human ion

channels as closely as possible might perhaps offer a way forwards.

Many researchers tried in vain. The breakthrough came from an unexpected direction. Roderick MacKinnon, after studying

biochemistry, turned to medicine and qualified as medical doctor. After working as a physician for some years, he grew so

interested in ion channels that he started to do research in the field: 襇y scientific career in effect began at the age of 30�, he

has admitted. But his career took off quickly. Realising that better and higher-resolution structures were needed for

understanding how ion channels function, he decided to learn the fundamentals of X-ray crystallography. It was then only a

few years before he astonished the whole research community by presenting a structure of an ion channel. This was in April

1998.

First ion channel mapped � atom by atom

In 1998, then, MacKinnon determined the first high-resolution structure of an ion channel, called KcsA, from the bacterium

Streptomyces lividans. MacKinnon revealed for the first time how an ion channel functions at atomic level. The ion filter,

which admits potassium ions and stops sodium ions, could now be studied in detail. Not only was it possible to unravel how the

ions passed through the channel, they could also be seen in the crystal structure � surrounded by water molecules just before

they enter the ion filter; right in the filter, and when they meet the water on the other side of the filter (fig. 4). MacKinnon

could explain why potassium ions but not sodium ions are admitted through the filter: namely, because the distance between

the potassium ion and the oxygen atoms in the filter is the same as that between the potassium ion and the oxygen atoms in the

water molecules surrounding the potassium ion when it is outside the filter. Thus it can slide through the filter unopposed.

However, the sodium ion, which is smaller than the potassium ion, can not pass through the channel. This is because it does not

fit between the oxygen atoms in the filter and therefore remains in the water solution. The ability of the channel to strip the

potassium ion of its water and allow it to pass at no cost in energy is a kind of selective catalysed ion transport.

The cell must also be able to control the opening and closing of ion channels. MacKinnon has shown that this is achieved by a

gate at the bottom of the channel which opened and closed a molecular 襰ensor�. This sensor is situated close to the gate.

Certain sensors react to certain signals, e.g. an increase in the concentration of calcium ions, an electric voltage over the cell

membrane or binding of a signal molecule of some kind. By connecting different sensors to ion channels, nature has created

channels that respond to a large number of different signals.

High resolution image (jpeg 137 kB) �

Fig 4. The ion channel permits passage of potassium ions but not sodium

ions. The oxygen atoms of the ion filter form an environment very similar

to the water environment outside the filter. The cell may also control

opening and closing of the channel.

High resolution image (jpeg 121 kB) �

OUTSIDE THE ION FILTER (A)

Outside the cell membrane the ions are bound to water molecules with certain distances to the oxygen atoms of the

water.

INSIDE THE ION FILTER (B)

For the potassium ions the distance to the oxygen atoms in the ion filter is the same as in water.

The sodium ions, which are smaller, do not fit in between the oxygen atoms in the filter. This prevents them from

entering the channel.

Understanding diseases

Membrane channels are a precondition for all living matter. For this reason, increased understanding of their function

constitutes an important basis for understanding many disease states. Dehydration of various types, and sensitivity to heat, are

connected with the efficancy of the aquaporins. The European heat waves of recent years, for example, resulted in many deaths

where the cause has sometimes been connected to problems in maintaining the body-fluid balance. In these processes the

aquaporins are of crucial importance.

Disturbances in ion channel function can lead to serious diseases of the nervous system as well as the muscles, e.g. the heart.

This makes the ion channels important drug targets for the pharmaceutical industry.

The Laureates

Peter Agre

Departement of Biological Chemistry

420 Physiology Building

Johns Hopkins University School of Medicine

725 North Wolfe Street

Baltimore Maryland 21205

USA

US citizen. Born 1949 (54 years) in Northfield, Minnesota,

USA. B.A. at Augsburg College, Minneapolis, chemistry major,

1970. M.D. at Johns Hopkins University School of Medicine in

Baltimore, 1974. Since 1993, Professor of Biological Chemistry

and Professor of Medicine at Johns Hopkins School of Medicine.

Roderick MacKinnon

Howard Hughes Medical Institute

Laboratory of Molecular Neurobiology and Biophysics

Rockefeller University

1230 York Avenue, New York,

New York 10021

USA

US citizen. 47 years, grew up in Burlington outside Boston,

USA. B.A. at Brandeis University, Boston, 1978. M.D. at Tufts

Medical School in Boston, 1982. Since 1996, Professor of

Molecular Neurobiology and Biophysics at The Rockefeller

University in New York.

The Official Web Site of The Nobel Foundation

Copyright� 2003 The Nobel

2003年两位研究细胞膜的美国科学家获诺贝尔化学奖2003　　

送交者: munchen 2003年10月08日

新浪科技讯：据路透社报道，美国科学家阿格里和麦克农因为对细胞膜的研究而获得了2003年度化学奖。对细胞

膜的研究有助于理解基本的生命进程。

　　瑞典皇家科学院星期三称，这两位美国科学家有关盐和水是如何在人类细胞内进出的发现“对于我们了解许多

疾病具有重要意义。”

　　54岁的阿格里在巴尔的摩的霍普金斯大学附属医院工作。47岁的麦克农在波士顿长大，在纽约的洛克菲勒大学的

休斯医学院工作。

　　瑞典皇家科学院称：“今年的诺贝尔化学奖颁发给两位发现盐和水是如何在人类细胞内进出的科学家。这一发

现使我们对分子的活动有了基本的理解，例如，我们的肾是如何从尿液中吸取水分、我们神经细胞内的电信号是如

何产生和传播的。”

　　1991年，阿格里发现了一个分子膜水通道。他的这一发现最后导致整个水通道家族的发现。学院称：“这一决

定性的发现为对水通道的生物化学、生理学和基因学的研究打开了大门。研究者可以对水分子经过细胞膜的整个

过程进行详细的研究，理解为什么只有水能通过，而其它小的分子则无法通过。这使医生对肾病有了更进一步的理

解。”

　　麦克农的贡献则在于盐通道方面，这种履盖整个隔膜的蛋白质为无机盐分子在细胞隔膜间的运动提供了通道。

它起到了大门和看门人的双重作用。盐通道控制着心率、调节荷尔蒙分泌、并产生神经系统信息传送所需要的电刺

激。

　　学院称“由于麦克农的贡献，我们现在能够看到盐通过各个通道流动，这些通道可以用不同的细胞信号所开启

和关闭。”

　　诺贝尔奖金首次于1901年颁发，是根据瑞典工业家诺贝尔的遗嘱所设立的。炸药的发明者诺贝尔于1896年去世。

每年的颁奖仪式于10月10月诺贝尔逝世纪念日在奥斯陆举行，奖金为1千万瑞典克朗(130万美元)。崐崐骑躅溽糸镱

加跟贴 发新贴 〖校友论坛索引首页〗