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in switching processes, the molecules mustbe mobile enough to respond quickly toexternal stimuli. High viscosity is a generalproblem of columnar phases, but it can bemuch reduced by adding solvents that dissolve around and between the flexiblechains11,12. As well as reducing viscosity, thiscan lead to a change of the organization inthe LC phase: in the case reported by Sawa-mura et al.2, the hexagonal columnar LCphase was replaced by a columnar ‘nematic’phase at higher solvent concentrations andtemperatures. In this phase, the long-rangehexagonal lattice is lost and the columns areonly on average aligned parallel to eachother. Nevertheless, these nematic phases
may also have special properties resultingfrom the polar order within the columns13.
Many of the advances in LC research havebeen stimulated by fresh designs of molec-ules that form new LC phases. In their ‘shut-tlecock’ molecules, Sawamura et al.2 haveundoubtedly provided a new design princi-ple for research teams to play with. ■
Carsten Tschierske is in the Department ofChemistry, Institute of Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes Strasse 2, D-06120 Halle/Saale,Germany. e-mail: [email protected]. Boden, N. & Movaghar, B. in Handbook of Liquid
Crystals Vol. 2B (eds Demus, D., Goodby, J., Gray, G. W., Spiess,
H. W. & Vill, V.) 781–798 (Wiley–VCH, Weinheim, 1998).
2. Sawamura, M. et al. Nature 419, 702–705 (2002).
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ecule, consisting of two identical chains ofabout 100 amino acids each, and neither ofthe two known receptors to which it binds isan ion channel. In fact, one BDNF receptor isan enzyme, the transmembrane tyrosinekinase TrkB, which, with a certain delay,mediates some of the typical biological activities of BDNF — such as the preventionof neuronal death3 (Fig. 1, overleaf). YetKonnerth and colleagues clearly showed thatBDNF causes rapid membrane depolariza-tion, and that briefly exposing TrkB-express-ing neurons to puffs of BDNF triggers trainsof action potentials2. Other neurotrophinsthat have different receptor specificitiesfailed to do this.
Although surprising, these resultshelped to explain previous observationsindicating that BDNF modulates synaptictransmission4 (neurons typically commu-nicate at synapses, which are specializedjunctions). One particularly famous exam-ple of such modulation is the long-termpotentiation (LTP) of synaptic transmis-sion. This is a widely used cellular model of memory, and numerous studies haveshown that in the hippocampus — a brainstructure crucial to memory formation inrodents and humans — BDNF plays a role in LTP that is essentially as signifi-cant as that of glutamate4. The observed BDNF-induced membrane depolarizationtriggered an increase in the levels of Ca2+
ions in the protrusions (spines) of post-synaptic neurons — those on the receivingside of the synapse — and immediatelyinduced LTP when paired with a burst ofsynaptic stimulation5.
In an impressive reconstitution experi-ment, Konnerth and colleagues1 now showwhich molecules are needed for BDNF torapidly depolarize neurons. Briefly, whenthe authors created fibroblast cells contain-ing a particular subtype of Na+ channel,Nav1.9, together with the BDNF receptorTrkB, they found that BDNF caused aninward flow of Na+ ions, and hence mem-brane depolarization, within milliseconds.This is simply too rapid to be attributed to the enzymatic activity of TrkB. Moreover,in these experiments, Nav1.9 could not be activated by voltage changes alone,although the related channel Nav1.7 could.So the explanation must be that binding toBDNF produces a conformational change in TrkB that is transferred without delay to Nav1.9, such that it briefly becomes permeable to Na+ ions. Finally, Konnerthand colleagues found that, in hippocampal neurons, the targeted elimination of Nav1.9 blocks BDNF-induced depolariza-tion. This implies that these neurons, atleast, contain Nav1.9 and require it for theBDNF-mediated influx of Na+ ions.
The unexpected conclusion that a secret-ed growth factor can modulate the opening(gating) of an ion channel on the same
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Figure 2 Examples of hexagonal lattices withpolar columns (coloured green and blue for thetwo orientations). Note that it is not possible toarrange the columns in such a manner that eachpolar column only has neighbours of theopposite polar direction.
Ion channels are remarkable proteins thatregulate the transfer of ions across the lipidbilayers that make up cellular membranes.
These proteins are required for a variety ofphysiological processes; for instance, a groupof cation-selective channels is responsiblefor conducting action potentials along nervecells, allowing them to transfer informationfrom one place to another. In vertebrates, theions that are typically responsible for thepropagation of action potentials are sodiumions. These are temporarily allowed to enter neurons through channels in the cellmembrane that open as a result of a trans-membrane voltage change. Surprisingly,however, Konnerth and colleagues1 nowreport (page 687 of this issue) that a brainprotein secreted by neurons is involved inopening a particular sodium channel — onealready known to occur in sensory neuronsof the peripheral nervous system.
The secreted protein in question is agrowth factor called brain-derived neuro-trophic factor (BDNF), and the story beganthree years ago when Konnerth and col-leagues2 found that BDNF causes membranedepolarization within milliseconds. (Mem-brane depolarization refers to a shift in thepotential difference across the membranethat, beyond a certain threshold, can triggeraction potentials.) This was a remarkablefinding because, until then, only neuro-transmitters had been found to have such arapid effect on the membrane potential of neurons. Typical neurotransmitters are low-molecular-weight compounds such asacetylcholine and the amino acids glutamateand glycine. They act on a millisecond time-scale because they bind to receptors that are also ion channels, causing them to open briefly.
By contrast, BDNF is a much larger mol-
Neurobiology
Neurotrophin channels excitementYves-Alain Barde
Sodium-ion channels usually open in response to a voltage change acrossthe membrane in which they sit. But, surprisingly, a growth factor secretedby neurons also rapidly triggers the opening of a specific sodium channel.
© 2002 Nature Publishing Group
timescale as a voltage change raises severalquestions. The Nav1.9 channel is best knownfor its presence in small sensory neurons ofthe dorsal-root and trigeminal ganglia6,where, together with Nav1.8, it may play a keypart in the physiology of neurons involved inpain perception6,7. The expression of Nav1.9is regulated by another growth factor, glial-cell-derived neurotrophic factor (GDNF).These sensory neurons do not express TrkB,so it will be interesting to see whether onecomponent of the GDNF receptor, the tyro-sine kinase Ret, is also associated withNav1.9, and whether GDNF causes rapidchanges in membrane potential. If so, thiscould have implications for our understand-ing of pain sensing.
In a similar vein, most Nav1.8-expressingand many Nav1.9-expressing neurons alsoexpress TrkA7 — the tyrosine kinase receptorfor nerve growth factor (NGF). NGF hasbeen associated with pain sensing in manyways8, and one wonders whether it may trigger the rapid opening of Nav1.8 or Nav1.9 via TrkA.
Another question is whether the BDNF-induced, TrkB-mediated depolarizationseen in all neurons of the central nervoussystem (CNS) tested so far can be attributedto Nav1.9. Although Konnerth and col-leagues’ latest report1 indicates that Nav1.9 is expressed by hippocampal CNS neurons,the levels of expression are probably muchlower than those in sensory neurons6. Finally, it has not yet been demonstratedbiochemically that TrkB associates directlywith Nav1.9, although TrkB does associatewith other transmembrane proteins3,9, suchas the neurotrophin receptor p75 and thenonspecific cation channel TRPC3 (Fig. 1).
Intriguingly, the binding of BDNF to TrkB also increased the permeability of the TRPC3 channel9, although this requiredthe enzymatic activity of TrkB and was considerably slower (minutes instead ofmilliseconds).
Thus, one of the last remaining distinc-tions between the physiological propertiesof neurotrophins and neurotransmittersseems to have disappeared. Work on neuro-transmitters may become a source of inspiration for researchers interested in theneurophysiology of neurotrophic factors,and one of the next questions may be howthe effects of BDNF on ion channels arerapidly inactivated. Mechanisms involvingreceptor internalization might be too slowto eliminate this poorly diffusible protein,which is also fairly resistant to protein-degrading enzymes. But BDNF-induceddesensitization, as occurs with neurotrans-mitter receptors, may be an attractive possibility to explore. ■
Yves-Alain Barde is at the Friedrich-MiescherInstitute for Biomedical Research, 4058 Basel,Switzerland.e-mail: [email protected]
1. Blum, R., Kafitz, K. W. & Konnerth, A. Nature 419, 687–693
(2002).
2. Kafitz, K. W., Rose, C. R., Thoenen, H. & Konnerth, A. Nature
401, 918–921 (1999).
3. Bibel, M. & Barde, Y.-A. Genes Dev. 14, 2929–2937
(2000).
4. Poo, M. M. Nature Rev. Neurosci. 2, 24–32 (2001).
5. Kovalchuk, Y., Hanse, E., Kafitz, K. W. & Konnerth, A. Science
295, 1729–1734 (2002).
6. Dib-Hajj, S., Black, J. A., Cummins, T. R. & Waxman, S. G.
Trends Neurosci. 25, 253–259 (2002).
7. Benn, S. C., Costigan, M., Tate, S., Fitzgerald, M. & Woolf, C.
J. Neurosci. 21, 6077–6085 (2001).
8. Apfel, S. C. Clin. J. Pain 16, 7–11 (2000).
9. Li, H.-S., Xu, S.-Z. S. & Montell, C. Neuron 24, 261–273
(1999).
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Figure 1 Brain-derived neurotrophic factor (BDNF) is a versatile protein. There are two receptors for BDNF on the surface of neurons: the neurotrophin receptor p75, which binds all neurotrophins,and TrkB. Each receptor alone binds BDNF with nanomolar affinity, but when they associate, the affinity and selectivity of TrkB for BDNF increase. TrkB can also associate with two different ion channels. TRPC3 is a non-selective cation channel that needs to be phosphorylated by TrkB to open; this is a slow process (acting in the range of minutes). Nav1.9 is selective for Na+ ions and, as Konnerth and colleagues1 show, opens within milliseconds following the binding of BDNF to TrkB. The figure also shows some of the functional outcomes of the activation of the BDNF receptors.
NeurotransmitterreleaseCell death
Increasedligand affinityand selectivity
NeuronalsurivivalDendriticbranching
Slow increasein permeabilityto cations
Very rapid increasein permeabilityto Na+ ions
BDNF TrkB
p75
TRPC 3
Nav1.9
100 YEARS AGOThe question I wish to bring to your noticeto-day is an old one: if two events happensimultaneously or one follows the other at a short interval of time, does this give us any reason to suppose that thesetwo events are connected with each other,both being due to the same cause, or onebeing the cause of the other? Everyoneadmits that the simple concurrence ofevents proves nothing, but if the samecombination recurs sufficiently often wemay reasonably conclude that there is a realconnection. The question to be decided ineach case is what is “sufficient” and what is “reasonable”. Here we must draw adistinction between experiment andobservation. … The cause of the differencelies in the fact that in an experiment we can control to a great extent all thecircumstances on which the result depends, and we are generally right inassuming that an experiment which gives a certain result on three successive days will do so always. But even this sometimesdepends on the fact that the apparatus is not disturbed, and that the housemaid has not come in to dust the room. Here liesthe difference.From Nature 16 October 1902.
50 YEARS AGOOur present political systems are likely to be modified. Democracy lacks survival value. The state of parasitism on thecommunity engendered by modern social conditions is impermanent because in the end the parasite destroys its host and then itself perishes: the process is likely to be hastened by the concomitantreduction of the more intelligent, these being now driven to have few or no children.It will be the non-parasitic communities thatwill survive, and those that multiply most will dominate the earth by sheer numbers.For this reason the author thinks that world agreement to control population could never be attained: an aggressor nation or bloc would never permit theirpeople to restrict their numbers, and othernations that wished to survive would have to follow suit. Government would possibly be by some “hero” who has sufficient senseto adapt himself to a society of densepopulation. Here intellect will count, butmorality may not, since “in a highlycompetitive world, the sinner has manyadvantages over the saint”.From Nature 18 October 1952.
© 2002 Nature Publishing Group
