J Physiol 588.11 (2010) pp 1821–1822 1821

EDITORIAL

Introduction to The Journal ofPhysiology’s Special Issue onNeurological Channelopathies

Brian RobertsonDeputy Editor in Chief, The Journal ofPhysiology

It gives me special pleasure to welcomereaders to this Journal of Physiology SpecialIssue on Channelopathies, and offer mythanks to the our distinguished organisingeditors, Professors Dimitri Kullmann andStephen Waxman, for their efforts in puttingthis exciting and important issue together.Almost no area of modern physiologybrings together so many different disciplinesworking together as the effort to under-stand the channelopathies. From structuralbiologists, biophysicists and neuroscientiststo clinicians (and not forgetting theall-important sufferers and their families),these disparate groups can all bring theirexpertise and tools to bear on unravellingthe puzzles offered by this wide range ofdiseases and disorders.

Here is an extract from a letter of WilliamHarvey, writing to the physician JohnVlackveld in 1657:

Nature is nowhere accustomed more openlyto display her secret mysteries than in caseswhere she shows traces of her workings apartfrom the beaten path; nor is there any betterway to advance the proper practice of medicinethan to give our minds to the discovery of theusual law of nature by careful investigation ofcases of rarer forms of disease.

Channelopathies provide a superbexample of this, and have become one ofthe most interesting areas of research overthe last couple of decades. And from ateaching point of view, these disorders offera fascinating route into physiology. I’veused the sad stories behind the unravellingof the molecular basis of Jervell andLange-Nielsen syndrome or the true lifecases of congenital insensitivity to pain toget biochemistry and even physics under-graduates ‘into’ potassium and sodiumchannels. Students and the general public(and I hesitate to say this, but researchersalso) are fascinated by detective storiesand diseases. Channelopathy researchencompasses both.

A scientific introduction to this SpecialIssue on channelopathies, provided by the

two investigators who were the drivingforce behind it, Dimitri Kullmann andSteve Waxman, invites readers to think.They concisely describe high points ofthe progress made since the first ionchannel mutations were linked to mono-genic neurological disease, posit that othernon-monogenic disorders of excitabilitymay arise from interplay of multiple genesincluding those that encode ion channels,and then put some timely issues andemerging concepts on the table.

The subsequent articles are from a widevariety of expert ‘channelopathologists’describing a selection of diseases from nerveand muscle.

Wimmer et al. (2010) focus on theaxon initial segment, which contains ahigh density of key voltage gated ionchannels, and describe how it may become ahotspot for epileptogenesis. Still on epilepsy,Rajakulendran et al. (2010) describe theresults of their studies of mutationsin CACNA1A, the gene encoding theprincipal subunit of the P/Q calciumchannel. Mutations here underlie episodicataxia type 2 (EA2). Interestingly, somepatients with episodic ataxia and epilepsyhave CACNA1A mutations. The authorsconclude that mutations in CACNA1Athat confer a loss of P/Q-type channelfunction are associated with episodic ataxiaand epilepsy. Meisler and her colleagues(2010) point out that sodium channelmutations can play a key role in humanepilepsies, with several hundred mutationsin SCN1A encoding the sodium channelNaV1.1 being the most common geneticcause of inherited and sporadic epilepsy.On the same topic, Catterall et al.(2010) propose a unified loss-of-functionhypothesis for the spectrum of epilepsysyndromes caused by genetic changes inNaV1.1 channels, where mild impairment ofsodium channel function underlies febrileseizures, and at the other end of thespectrum, with complete loss of functionleading to intractable epileptic seizures.Of course, epilepsies may also be causedby changes in receptor-channel function,and Macdonald et al. (2010) give a reviewof how mutations in several inhibitoryGABAA receptor subunit genes (GABRA1,GABRB3, GABRG2 and GABRD) also leadsto different types of epilepsy, ranging fromchildhood absence epilepsy to generalizedepilepsy with febrile seizures. The mutations

in GABAA genes vary, and can lead toalterations in receptor-channel functiondirectly or trafficking and folding problems.Still in the brain, Daniela Pietrobon (2010)discusses experiments with transgenic mice,which serve as a model for familial hemi-plegic migraine type 1 (FHM1). FHM1is a subtype of migraine associated withaura, and is caused by mutations in CaV2.1(P/Q-type) Ca2+ channels.

Of course, it is not only the CNS that showschannelopathies. Skeletal muscles are alsoaffected, and this issue has two reviews onthe current state of play of research here.Matthews & Hanna (2010) focus on hypo-kalaemic periodic paralysis (hypoPP), witha discussion of potential clinical therapies.Steve Cannon (2010) describes in somedetail the missense mutations at arginineresidues in S4 voltage sensors of of theskeletal sodium channel NaV1.4, which leadto a ‘gating pore current’ causing hypoPP.

Cregg et al. (2010) review how a carefulstudy of channelopathies helps us to under-stand pain pathways, and perhaps offer cluesto novel therapeutics to deal with the majorhealth problems associated with pain.

Last but not least, Steve Waxman’s group(in a Special Issue related paper, Estacionet al. 2010) show some of their resultswith automated patch clamp technology,employed by them to screen previouslyundescribed mutations in the NaV1.7sodium channel (S211P), which causeserythromelalgia.

There is a lot in this Special Issue, for awide range of readers; I hope that you willenjoy and learn as much from the articles asI did.

References

Cannon SC (2010). Voltage-sensor mutations inchannelopathies of skeletal muscle. J Physiol588, 1887–1895.

Catterall WA, Kalume F & Oakley JC (2010).NaV1.1 channels and epilepsy. J Physiol 588,1849–1859.

Cregg R, Momin A, Rugiero F, Wood JN & ZhaoJ (2010). Pain channelopathies. J Physiol 588,1897–1904.

Estacion M, Choi JS, Eastman EM, Lin Z, Li Y,Tyrrell LJ, Yang Y, Dib-Hajj SD & Waxman SG(2010). Can robots patch-clamp as well ashumans? Characterization of a novel sodiumchannel mutation. J Physiol 588, 1915–1927.

C© 2010 The Author. Journal compilation C© 2010 The Physiological Society DOI: 10.1113/jphysiol.2010.191114

1822 Editorial J Physiol 588.11

Macdonald RL, Kang J-Q & Gallagher MJ(2010). Mutations in GABAA receptorsubunits associated with genetic epilepsies.J Physiol 588, 1861–1869.

Matthews E & Hanna MG (2010). Musclechannelopathies: does the predicted channelgating pore offer new treatment insights forhypokalaemic periodic paralysis? J Physiol588, 1879–1886.

Meisler MH, O’Brien JE & Sharkey LM (2010).Sodium channel gene family: epilepsymutations, gene interactions and modifiereffects. J Physiol 588, 1841–1848.

Pietrobon D (2010). Insights into migrainemechanisms and CaV2.1 calcium channelfunction from mouse models of familialhemiplegic migraine. J Physiol 588,1871–1878.

Rajakulendran S, Graves TD, Labrum RW,Kotzadimitriou D, Eunson L, Davis MB,Davies R, Wood NW, Kullmann DM, HannaMG & Schorge S (2010). Genetic andfunctional characterisation of the P/Q calciumchannel in episodic ataxia with epilepsy.J Physiol 588, 1905–1913.

Wimmer VC, Reid CA, So EY-W, Berkovic SF &Petrou S (2010). Axon initial segmentdysfunction in epilepsy. J Physiol 588,1829–1840.

C© 2010 The Author. Journal compilation C© 2010 The Physiological Society