mine either the transition temperature or thethermodynamic characteristics. The materi-al’s properties instead depend on two energygaps (Fig. 1), one that would correspond to atransition temperature of 45 K, the other to atransition temperature of 15 K. Operating inconcert, they lead to a transition tempera-ture of 39 K. These calculated values3,5 are

probably more accurate than, although con-sistent with, estimates from thermodynamicand spectroscopic experiments.

The two-band model of superconduc-tivity has been a theorists’ pet for fourdecades, but until now has remained justthat. Kondo6 suggested two-band supercon-ductivity driven by electron–electron repul-sion which would be possible if the two gapshave opposite signs. But there is no evidencethat this picture is relevant to MgB2. On theother hand, Leggett7 predicted that a two-band character would lead to a quantum-mechanically induced oscillation betweenelectron pairs that possess different bindingenergies corresponding to the two gaps. Thepossibility of observing this effect in MgB2 isbeing assessed8.

It is clear that MgB2 is a new breed ofsuperconductor, and other intermetalliccompounds might also superconduct in thesame way9. Another new breed is the smallclass of ferromagnets that show supercon-ductivity10 — a property long thoughtimpossible. It seems that all we can reallycount on is that new superconductors willcontinue to appear in unexpected ways. ■

Warren Pickett is in the Department of Physics,University of California, Davis, California 95616, USA.e-mail: pickett@physics.ucdavis.edu

1. Nagamatsu, J., Nakagawa, N., Muranaka, T., Zenitani, Y. &

Akimitsu, J. Nature 410, 63–64 (2001).

2. Grant, P. Nature 411, 532–533 (2001).

3. Choi, E. J., Roundy, D., Sun, H., Cohen, M. L. & Loule, S. G.

Nature 418, 758–760 (2002).

4. Liu, A. Y., Mazin, I. I. & Kortus, J. Phys. Rev. Lett. 87, 087005

(2001).

5. Golubov, A. A. et al. J. Phys. Cond. Mater. 14, 1353–1360

(2002).

6. Kondo, J. Prog. Theor. Phys. 29, 1–9 (1963).

7. Leggett, A. J. Prog. Theor. Phys. 36, 901–930 (1966).

8. Sharapov, S. G., Gusynin, V. P. & Beck, H. Preprint cond-

mat/0205131 (2002); http://xxx.lanl.gov

9. Rosner, H., Kitaigorodsky, A. & Pickett, W. E. Phys. Rev. Lett.

88, 127001 (2002).

10.Saxena, S. S. et al. Nature 406, 587–592 (2000).

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high transition temperature by breaking the rules.

Conventional materials superconductwhen electrons form pairs (‘Cooper pairs’).In MgB2, the pairing arises from attractiveinteractions between the electrons that aremediated by atomic vibrations, or phonons.This has been verified by isotopic replace-ment experiments and explained in somedetail by several computational groups. Butunlike previously known good supercon-ductors, MgB2 does not have a high charge-carrier density; only simple s- and p-shellelectrons are involved in its superconductivi-ty; and it has a non-cubic crystal structure.Other features make MgB2 even moreremarkable: only a few of the atomic-vibra-tion modes are involved in its ability tosuperconduct, and only about half of itscharge carriers are strongly affected duringsuperconductivity.

Polycrystalline samples of MgB2 can beprepared fairly easily, but the lack of single-crystal samples — which have been madeunder pressure only recently — has delayeddefinitive experimental results. However,decades of computational research intomaterials and the fact that MgB2 is, bothstructurally and electronically, a simplematerial, have led to many of the questionsabout its superconductivity being addressedand answered by computational means. Theresults of Choi et al.3 are the most detailed to date, and are the first to reveal the fullstructure of a fundamental feature of super-conductors, the energy gap.

The energy gap is the binding energy thatinduces electrons to form pairs, and it isdirectly related to the material’s transitiontemperature. It determines the thermo-dynamic behaviour of the superconductorand influences its properties when used indevices (for example, pair tunnelling inJosephson junctions). In most known super-conductors, the size of the energy gap variesonly slightly for the various electron pairsinvolved in the superconductivity — it isconsidered to be isotropic. But for MgB2, theenergy gap seems to be anisotropic — it hastwo different bands, that is, two differentbinding energies for electron-pair forma-tion. This feature has been suggested by sev-eral groups and calculated by Liu et al.4 andby Golubov et al.5 in a simplified form. Choiet al.3 now confirm this picture in detail.

The two-band character of MgB2 meansthat we must adjust our ideas on supercon-ductivity. According to the usual picture, themain characteristics of a superconductor —its critical temperature and energy gap — aredetermined by a coupling strength, a repul-sion strength and one or two representativevibrational frequencies. For a two-bandsuperconductor the picture is much richer:there are four coupling strengths and fouranalogous repulsion strengths; but the aver-age coupling strength is insufficient to deter-

Signal transduction

Positive feedback from coffeeJean-Marie Vaugeois

Caffeine acts on our nerve cells to wake us up. It turns out that it does sothrough a molecular signalling pathway that involves a positive feedbackloop, boosting caffeine’s effects from inside the cell.

Have you ever wondered why coffee issuch an effective pick-me-up? Theanswer has been gradually coming into

focus over the past few years, thanks tonumerous studies of the brain regions andneuronal molecules affected. With the workreported by Lindskog and colleagues1 onpage 774 of this issue, much of the fine detailhas been filled in.

In broad terms, the effects of caffeine onthe body have been known for several years.

At the concentrations reached during habit-ual coffee consumption, caffeine is thoughtto bind to and block two proteins — the A1

and A2A receptors — on the surface of certainnerve cells that control voluntary move-ments. This means that the receptors can nolonger detect the neuromodulator adeno-sine, which results in a long-lasting decreasein the activity of inhibitory neurons, andhence more movement, in rodents2.

Early evidence for this theory came in

Figure 1 Double-gap superconductor. The‘energy gap’ in a material reflects how easily itselectrons form superconducting pairs, and so is related to the transition temperature up towhich the material is superconducting.Conventionally, superconductors have a singleenergy gap in the spectrum of unpaired-electronstates, for example the single gap indicated bythe dashed lines here. The states in the normal(non-superconducting) phase are ‘pushed out’ of the gap region, leaving a sharp peak on either side of the gap. Choi et al.3 demonstrate,however, that magnesium diboride has twoenergy gaps, one corresponding to a transitiontemperature (Tc) of 45 K (blue), the other to 15 K (red). The result is a compromise transition temperature for the bulk material of 39 K — an unusually high value for a material that is not a high-temperature, copper-oxide superconductor.

00

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Energy gap Tc = 15 KEnergy gap Tc = 45 K

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© 2002 Nature Publishing Group

1995, when Svenningsson, Nomikos andFredholm3 found that the stimulatory effectsof caffeine are strongly correlated with thereduced expression of certain genes thatwould normally be switched on in responseto activation of the A2A receptor by adeno-sine. More support came from studies ofmice engineered to lack this receptor4. More-over, A2A-receptor blockers are being devel-oped as potential treatments for Parkinson’sdisease, and there is evidence that caffeinecan help to protect against the nerve degen-eration associated with this disease5. So theidea that caffeine works by blocking the A2A

receptors seems well established.But how does this lead to a stimulant

effect? To understand this, we need first tolook at the effects of adenosine on neurons(Fig. 1a). As mentioned above, adenosine is atype of neuromodulator, a molecule thatfine-tunes the effects of the chemicals —neurotransmitters — that nerve cells use tocommunicate. Neuromodulators often dothis by binding to receptors that are in turncoupled to common molecular switches,called G proteins, within neurons. Both neurotransmitters and neuromodulatorsproduce many of their effects through com-plex, slow signalling pathways that modifyother neuronal proteins by the addition andremoval of phosphate groups (phosphoryla-tion and dephosphorylation, respectively)6.This can change the physiological propertiesof the target proteins, which might be otherreceptors, ion channels or pumps, or gene-transcription factors.

For instance, by binding to and activatingthe G-protein-coupled A1 or A2A receptors,adenosine can control the enzyme adenylylcyclase in opposite ways, with the A2A recep-tors stimulating the enzyme and therebyleading to production of the messenger mol-ecule cyclic AMP (cAMP). This eventuallyleads, via a cascade of protein modification,to the increased transcription of certaingenes, to an expression level that is correlatedwith reduced motor activity. One proteincascade involves the enzyme protein kinaseA, which is activated by cAMP and which inturn phosphorylates the DARPP-32 proteinin a subgroup of neurons in the striatum7 —a brain region that controls motor activity.

Lindskog et al.1 now provide compellingevidence for a role of DARPP-32 in mediat-ing the effects of caffeine (Fig. 1b). Theauthors found that A2A receptors are presentin about half of the striatal neurons that con-tain DARPP-32. They next showed that themotor effects of caffeine depend on DARPP-32, as the effects were not seen in mice lack-ing this protein. Interestingly, however, thisdependence could be overcome by increas-ing the dose of caffeine.

How can these effects of DARPP-32 beexplained? Protein kinase A phosphorylatesthis protein at the amino acid threonine atposition 34. That turns DARPP-32 into an

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NATURE | VOL 418 | 15 AUGUST 2002 | www.nature.com/nature 735

Figure 1 How coffee wakes up your nerve cells, based on work by Lindskog et al.1. a, In the absence of caffeine. By activating A2A receptors, adenosine increases adenylyl cyclase activity, leading to the formation of cyclic AMP and activation of protein kinase A. This enzyme in turn activates protein phosphatase-2A, leading to dephosphorylation of DARPP-32 at threonine 75 (T75). Proteinkinase A also phosphorylates other target proteins. Finally, it phosphorylates DARPP-32 at T34,leading to the inhibition of protein phosphatase-1, which thus cannot dephosphorylate targetproteins7. b, Partial blockade of A2A receptors by low caffeine levels reduces the formation of cyclic AMP and the activation of protein kinase A, and hence of protein phosphatase-2A. Theresulting increased phosphorylation of T75 converts DARPP-32 into an inhibitor of protein kinase A. This amplifies the effects of caffeine by a positive feedback loop. High caffeine levelsvirtually abolish the activation of protein kinase A. Further phosphorylation sites at serine aminoacids add to the sophistication of DARPP-32 (not shown). CGS 21680, butyrolactone, okadaic acidand SCH 58261 are drugs used by Lindskog et al. to study these pathways. Thicker arrows and bars,and darker colours, indicate higher levels of activity.

AdenosineCGS 21680

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A2Areceptor

Proteinphosphatase-2A

Proteinphosphatase-2A

Proteinphosphatase-1

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inhibitor of a certain protein-dephosphory-lating enzyme (a protein phosphatase). Butwhen another amino acid in DARPP-32, thethreonine at position 75, is phosphorylated,the protein becomes an inhibitor of proteinkinase A itself (Fig. 1b). So does caffeine leadto an increase in phosphorylation of threo-nine 75? Lindskog et al. show that it does, asdoes a drug that specifically blocks the A2A

receptor. And how exactly does this occur?The authors find that caffeine does notincrease the constitutive activity of the neu-ronal Cdk5, an enzyme that phosphorylatesDARPP-32 at threonine 75. This result andother data suggest that caffeine insteadinhibits protein phosphatase-2A, preventingthis enzyme from dephosphorylating threo-nine 75. That results in a higher level ofDARPP-32 that is phosphorylated at thisamino acid.

All of which leads to the following model.With low doses of caffeine, only a little cAMPis produced by adenylyl cyclase; proteinkinase A is activated only weakly and cannotactivate protein phosphatase-2A. So threo-nine 75 on DARPP-32 remains phosphory-lated, and this protein in turn furtherinhibits protein kinase A, forming a positive

feedback loop. Such inhibition leads to a lowlevel of phosphorylation on target proteinsthat regulate nerve activity. (This is becausethe ability of protein kinase A to phosphory-late these proteins is reduced, and becauseprotein kinase A cannot phosphorylateDARPP-32 on threonine 34, which thereforecannot deactivate a phosphatase that alsoworks on the target proteins.) Caffeine hassome, although weak, effects in mice lackingDARPP-32. So Lindskog et al. suggest thatthis protein is not essential for, but ratherintensifies and prolongs, the effects of lowdoses of caffeine.

Higher doses of caffeine would produce along-lasting blockage of A2A receptors, abol-ishing the adenosine-signalling pathway andin particular the activity of protein kinase Ato the extent that no feedback loop would berequired to inhibit this enzyme further. Inother words, everything cooperates to abol-ish protein kinase A activity, leading to thelowest possible amounts of phosphorylatedtarget proteins. So, behavioural responses tocaffeine ultimately result from the activity ofnon-phosphorylated target proteins.

Of course, so far all of this work has beendone in rodents. We don’t yet know the

© 2002 Nature Publishing Group

Some of the consequences of the motionof Earth’s tectonic plates are quite evi-dent: various mountain chains for

instance. Others, such as events occurringdeep in subduction zones where one plateplunges beneath another, can be seen only

indirectly through seismic imaging tech-niques. The approach allows the structure ofEarth’s interior to be reconstructed fromobserved seismograms, and it continues topay dividends.

An example appears on page 763 of this

issue, where Levin et al.1 argue that they havedetected two instances of break-up of a sub-ducting slab at the junction of two oceanicplates. There are indications2,3 that slab dis-integration has occurred where oceanic andcontinental plates collide. But because earth-quake activity is uniformly distributed withdepth in subducting oceanic plates, it hadseemed that purely oceanic plates maintaintheir integrity.

Levin et al. imaged the structure of theupper 200 km of Earth’s mantle in the north-west Pacific, in the complex setting where theAleutian and Kamchatka subduction zonesmeet (Fig. 1). South of the junction beneathKamchatka, they identified a high-velocityfeature co-located with earthquakes. Thisthey interpret as cool, rigid subductingoceanic plate. North of the junction, veloci-ties were slower than average, with no evi-dence of deep earthquakes, the implicationbeing that there is no subducting slab there.This is an unexpected finding. In the past,subduction also occurred further north, theplate concerned being generated by ocean-floor spreading in the Komandorsky basin(Fig. 1a). If oceanic plates are rigid, the previ-ously subducted plate north of the junctionshould still be attached to the Komandorskybasin, which has remained at the surface.

Levin and colleagues’ conclusion is thatthe missing plate has broken off anddescended deep into the mantle (Fig. 1b).Subduction zones are regions where Earth’ssurface returns to cool the hot interior.Counterintuitively, they are also the site ofvolcanism. The melting of rocks in Earth’sinterior that is required for this volcanism isthought to result from the entry of hydrousfluids into the hot overlying mantle from the descending oceanic crust4–6. North of thejunction lie volcanoes that are now extinct,and the inferred absence of oceanic crustthere is taken by Levin et al. as an explana-tion: there is now no source of water to pro-mote magmatism. The volcanoes have beenextinct for at least five million years, so theplate must have become detached beforethen, taking oceanic crust away with it. If theplate continued its descent at the velocity ofthe Kamchatka slab (about 9 cm yr11), andassuming a dip of 457 or so, then in five mil-lion years it would have travelled 450 km andreached a depth of at least 300 km — beneaththe region surveyed by Levin and colleagues.

Where oceanic and continental platesmeet, the force that breaks a subducting slabis generated by the tendency of the buoyantcontinent to remain at the surface and that ofdense oceanic plate to continue its descent.In the case studied by Levin et al., if the frag-ment that was broken off was joined along itssouthern side to the subducting Pacific plate,then the driving force for detachment isclear: the much larger Pacific plate wouldhave pulled the fragment down. Joining ofthe plates is not required, though, especially

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736 NATURE | VOL 418 | 15 AUGUST 2002 | www.nature.com/nature

Earth science

Breaking platesJ. Huw Davies

Seismic images suggest that oceanic plates in the northwest Pacific brokeapart as they descended into Earth’s mantle. That might explain the highmagma output of some volcanoes in the region, and why others are extinct.

equivalent doses of caffeine in human terms:the answer will await the ability to usepositron emission tomography to study theoccupancy of the A2A receptor by caffeine inpeople’s brains. But, from the informationavailable so far, it seems likely that the con-centrations of caffeine used by Lindskog etal.1 are similar to those reached in our brainsafter a few cups of coffee. So the authors haveled us to the heart of the matter: DARPP-32keeps us going till the next coffee break byextending the effects of the last cup. Futureefforts will identify the target proteins thatare regulated by this signalling cascade.Together with insights gained from miceengineered to lack other intracellular sig-nalling molecules, this knowledge should

provide an even better understanding of caffeine’s effects. So, wake up, smell the freshcoffee and enjoy its effects for a long time,thanks to your dependable DARPP-32! ■

Jean-Marie Vaugeois is in the Unit of ExperimentalNeuropsychopharmacology, Faculty of Medicine andPharmacy, Université de Rouen, 22 BoulevardGambetta, 76183 Rouen Cedex 1, France.e-mail: jean-marie.vaugeois@univ-rouen.fr1. Lindskog, M. et al. Nature 418, 774–778 (2002).

2. Fredholm, B. B., Battig, K., Holmen, J., Nehlig, A. & Zvartau,

E. E. Pharmacol. Rev. 51, 83–133 (1999).

3. Svenningsson, P., Nomikos, G. G. & Fredholm, B. B. J. Neurosci.

15, 7612–7624 (1995).

4. Ledent, C. et al. Nature 388, 674–678 (1997).

5. Chen, J.-F. et al. J. Neurosci. 21, RC143 (1995).

6. Greengard, P. Science 294, 1024–1030 (2001).

7. Svenningsson, P. et al. Proc. Natl Acad. Sci. USA 97, 1856–1860

(2000).

Figure 1 Tectonics in the northwest Pacific. a, A view from Siberia looking towards the Pacific, andinterpretation of events 5–10 million years ago. The Pacific oceanic plate descends beneath south and central Kamchatka (blue), whereas plate produced by spreading in the Komandorsky basindescends beneath north Kamchatka (green). The green triangles show volcanoes then active. b, The Aleutian–Kamchatka junction today, interpreted from the work of Levin et al.1. The platebeneath north Kamchatka seems to have broken off and fallen deep into the mantle. Volcanismusually occurs above subduction zones, the likely cause being water released from descended oceanic crust which enters the mantle and promotes melting. Levin et al. regard the lack of oceanic crust in the region above this detached segment as an explanation for the now-extinctoverlying volcanoes (green triangles). The authors1 also argue that a second segment of platedetached at depth beneath central Kamchatka, leading to stronger mantle upflow and the exceptional magma output of the Klyuchevskoy volcano. The red triangles indicate active volcanoes. KB, Komandorsky basin; KSZ, Kamchatka subduction zone; ASZ, Aleutian subductionzone; KV, Klyuchevskoy volcano.

© 2002 Nature Publishing Group