Reviews of Physiology, Biochemistry and Pharmacology, Vol. 167

143 Pages·2014·2.946 MB·English

by  Bernd Nilius, Thomas Gudermann, Reinhard Jahn, Roland Lill, Stefan Offermanns, Ole H. Petersen (eds.)

Reviews
of Physiology,
Biochemistry and
Pharmacology
167
Reviews of Physiology, Biochemistry
and Pharmacology
More information about this series at
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(cid:1) (cid:1) (cid:1)
Bernd Nilius Thomas Gudermann Reinhard Jahn
(cid:1) (cid:1)
Roland Lill Stefan Offermanns Ole H. Petersen
Editors
Reviews of Physiology,
Biochemistry and
Pharmacology
167
Editors
BerndNilius ThomasGudermann
KULeuven Ludwig-Maximilians-Universita¨tMu¨nchen
Dept.ofCell.andMolecularMedicine MedizinischeFakulta¨t
LaboratoryofIonChannelResearch Walther-Straub-Institutfu¨rPharmakologie
B-3000Leuven Mu¨nchen
Belgium Germany
ReinhardJahn RolandLill
Max-Planck-InstituteforBiophysical UniversityofMarburg
Chemistry Inst.ZytobiologieundZytopathologie
Go¨ttingen Marburg
Germany Germany
StefanOffermanns OleH.Petersen
Max-Planck-Institutfu¨rHerzund SchoolofBiosciences
Lungen CardiffUniversity
AbteilungII MuseumAvenue
BadNauheim Cardiff,UK
Germany
ISSN0303-4240 ISSN1617-5786(electronic)
ISBN978-3-319-11920-5 ISBN978-3-319-11921-2(eBook)
DOI10.1007/978-3-319-11921-2
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Contents
TheTRPA1ChannelinInflammatoryandNeuropathicPain
andMigraine ................................................................... 1
RominaNassini,SerenaMaterazzi,SilviaBenemei,andPierangeloGeppetti
GlialCalciumSignallinginAlzheimer’sDisease ........................... 45
DmitryLim,VirginiaRonco,AmbraA.Grolla,AlexeiVerkhratsky,
andArmandoA.Genazzani
The“Sweet”SideofIonChannels ........................................... 67
JoannaLazniewskaandNorbertWeiss
CardiacFunctionsofVoltage-GatedCa2+Channels:Roleofthe
PharmacoresistantType(E-/R-Type)inCardiacModulation
andPutativeImplicationinSuddenUnexpectedDeath
inEpilepsy(SUDEP) ......................................................... 115
EtienneE.Tevoufouet,ErastusN.Nembo,MaxineDibue´-Adjei,
Ju¨rgenHescheler,FilomainNguemo,andToniSchneider
v
RevPhysiolBiochemPharmacol(2014)167:1–44
DOI:10.1007/112_2014_18
©Springer-VerlagBerlinHeidelberg2014
Publishedonline:26March2014
The TRPA1 Channel in Inflammatory
and Neuropathic Pain and Migraine
RominaNassini,SerenaMaterazzi,SilviaBenemei,
andPierangeloGeppetti
Abstract The transient receptor potential ankyrin 1 (TRPA1), a member of the
TRPsuperfamilyofchannels,isprimarilylocalizedtoasubpopulationofprimary
sensory neurons of the trigeminal, vagal, and dorsal root ganglia. This subset of
nociceptorsproducesandreleasestheneuropeptidessubstanceP(SP)andcalcito-
nin gene-related peptide (CGRP), which mediate neurogenic inflammatory
responses. TRPA1 is activated by a number of exogenous compounds, including
moleculesofbotanicalorigin,environmentalirritants,andmedicines.However,the
mostprominentfeatureofTRPA1residesinitsuniquesensitivityforlargeseriesof
reactive byproducts of oxidative and nitrative stress. Here, the role of TRPA1 in
modelsofdifferenttypesofpain,includinginflammatoryandneuropathicpainand
migraine,issummarized.SpecificattentionispaidtoTRPA1asthemaincontrib-
utingmechanismtothetransitionofmechanicalandcoldhypersensitivityfroman
acute to a chronic condition and as the primary transducing pathway by which
oxidative/nitrative stress produces acute nociception, allodynia, and hyperalgesia.
AseriesofmigrainetriggersormedicineshavebeenreportedtomodulateTRPA1
activityandtheensuingCGRPrelease.Thus,TRPA1antagonistsmaybebeneficial
inthetreatmentofinflammatoryandneuropathicpainandmigraine.
Keywords Migraine(cid:1)Nociceptors(cid:1)Pain(cid:1)TRPA1
Contents
1 TRPChannelsandSensoryNeurons.......................................................... 2
1.1 TRPChannels:StructureandMechanismofActivation............................... 2
1.2 TRPChannelsandNociceptors......................................................... 3
R.Nassini,S.Materazzi,S.Benemei,andP.Geppetti(*)
PharmacologyandOncologyUnit,DepartmentofHealthSciences,UniversityofFlorence,
VialePieraccini,6,50139Florence,Italy
e-mail:geppetti@unifi.it
2 R.Nassinietal.
2 TRPA1Channel.............................................................................. 4
2.1 StructureandFunctions................................................................ 5
2.2 NeuronalandExtra-NeuronalLocalization........................................... 6
2.3 TRPA1Agonists........................................................................ 7
2.4 ExogenousAgonists.................................................................... 8
2.5 EndogenousAgonists.................................................................. 10
2.6 ThermalandMechanicalActivation................................................... 12
2.7 TRPA1Antagonists.................................................................... 13
3 TRPA1andInflammatoryPain.............................................................. 15
3.1 ModelsofInflammatoryPain.......................................................... 16
4 TRPA1andNeuropathicPain................................................................ 19
4.1 NerveInjuryandDiabetesPainfulNeuropathy....................................... 20
4.2 Chemotherapeutic-InducedNeuropathy............................................... 21
5 TRPA1andMigraineHeadache............................................................. 23
5.1 TRPA1isActivatedbyMigraine-ProducingAgents................................. 24
5.2 AnalgesicandAntimigraineDrugsActbyTRPA1Targeting....................... 26
6 AdditionalPathophysiologicalRolesofTRPA1RelatedtoPrimarySensoryNeurons... 27
6.1 TheAirways............................................................................ 27
6.2 TheGastrointestinalTract.............................................................. 28
6.3 TheUrinaryTract...................................................................... 29
6.4 ItchandSkinInflammation............................................................ 29
7 Conclusions................................................................................... 30
References........................................................................................ 30
1 TRP Channels and Sensory Neurons
The original discovery that vision in Drosophila is produced by an initial
activation of a transient inward current associated with receptor stimulation
(MontellandRubin1989)hasled,withanunprecedentedpace,totheidentifica-
tion of the transient receptor potential (TRP) channels. TRPs represent one of
the largest families of ion channels with more than 56 subtypes, which are
widely distributed within the phylogeny where they contribute to an array of
different physiological functions and are implicated in a series of pathological
conditions.Inmammals,TRPscomprise28membraneproteinsmainlybehaving
as non-selective cation permeable channels. TRPs are classified into seven
subfamilies: TRPC (‘Canonical’), TRPV (‘Vanilloid’), TRPM (‘Melastatin’),
TRPP (‘Polycystin’), TRPML (‘Mucolipin’), TRPA (‘Ankyrin’), and TRPN
(‘NOMP-C’)(seealso(Nilius2007)).
1.1 TRP Channels: Structure and Mechanism of Activation
TRP’s general structure recapitulates that of voltage-gated channels with six
transmembrane domains (S1-6) and the intracellular N- and C-terminal regions
of variable length with a pore loop between S5 and S6 (Owsianik et al. 2006;
Nilius 2007). It has been reported that four subunits, each composed of six
TheTRPA1ChannelinInflammatoryandNeuropathicPainandMigraine 3
transmembranedomains,mayassembleinhomo-and/orhetero-tetramerstoform
thefunctionalchannel,whereeachsubunitcontributestoasharedselectivityfilter
andion-conductingpore(Schaefer2005).Beyondtheirgeneralmembranetopol-
ogyandpermeabilitytocations,TRPchannelsarestrikinglydiverseandexhibita
widevarietyofmodesofactivationbychemicalandphysicalstimuli(exogenous
chemical compounds, lipids, oxidative stress, acids, pheromones, osmolarity,
mechanical stimulation, light, temperature, and others), regulatory mechanisms
(transcription, alternative splicing, glycosylation, phosphorylation), and tissue
distribution (virtually all cells tested express at least one member of the super-
family). These features underline the unprecedented diversity of physiological
and pathophysiological functions mediated by TRPs and their definition as
polymodalsensors.
1.2 TRP Channels and Nociceptors
TRP channels are expressed in cellular membranes, with the exception of the
nuclear envelope and mitochondria, of almost every excitable and non-excitable
celltype.Theobjectofthepresentreviewisfinalizedtodescribephysiologicaland
pathophysiologicalfunctionsoftheTRPchannelslocalizedtoasubsetofprimary
sensoryneurons(Szallasietal.2007),wheretheyresulthighlyinvolvedinsensing
physiological and noxious agents and, more generally, in pain perception. Just
aboutacenturyago,Sherringtonproposedtheexistenceofnociceptors,asubgroup
ofprimarysensoryneuronswhichareactivatedbytissuedamagingstimuli,suchas
heat, intense pressure, or irritant chemicals, but not by innocuous stimuli such as
warmingorlighttouch(Sherrington1906;JuliusandBasbaum2001).Thehetero-
geneous population of primary sensory neurons and the fibres that they originate
canbedifferentiatedaccordingtomorphological,electrophysiological,neurochem-
ical, functional, andothercriteria.Inparticular,neuronswith thelargestdiameter
cell body give rise to myelinated, rapidly conducting Aβ fibres, which detect
innocuousstimuliandnormallydonotcontributetonociceptivestimulustransduc-
tion.Incontrast,neuronswithsmall-andmedium-diametercellbodiesgiveriseto
un-myelinated, slowly conducting C-fibres and thinly myelinated, more rapidly
conducting Aδ-fibres. Both are highly involved in nociception. Aδ- and
C-nociceptive fibres either respond to a single type of physical stimuli, or more
commonly integrate and generate responses to potentially damaging thermal,
mechanical, and/or chemical stimuli, and for this reason are also defined as
polymodalnociceptors(JuliusandBasbaum2001).
Aspecific subsetofC-fibre andAδ-fibrenociceptors isexquisitelysensitiveto
capsaicin,thepungentingredientinhotpeppers,andforthisreasontheyhavebeen
labelled as ‘capsaicin-sensitive’ sensory neurons. The selective excitatory role of
capsaicin is associated in a time- and concentration/dose-dependent manner with
the ability of the compound to desensitize the channel and to defunctionalize
TRPV1-positive nociceptors to capsaicin itself and to any other stimulus. This
4 R.Nassinietal.
uniquepropertyofcapsaicinmostlikelyderivesfromexcessiveCa2+influxthrough
thechannel,which,inadultratstransientlyandinnewbornratspermanently,alters
nociceptormorphologyandfunctioning(BevanandSzolcsanyi1990;Szallasiand
Blumberg 1999; Szallasi et al. 2007; O’Neill et al. 2012). This pharmacological
property of capsaicin to produce non-specific nociceptor defunctionalization has
been exploited therapeutically for topical treatment of patients affected by neuro-
pathicpainofviralorigin(Backonjaetal.2008).
TRPV1-expressing neurons comprise a subcategory defined as peptidergic
because they produce the neuropeptides calcitonin gene-related peptide (CGRP)
andthetachykinins,substanceP(SP)andneurokininA(NKA),whichinresponse
to depolarization, capsaicin or other excitatory stimuli, are released from central
andperipheralneuronalterminals.Uponperipheralneuropeptiderelease,activation
of CGRP and tachykinin (NK , NK and NK ) receptors on effector cells, partic-
1 2 3
ularlyatthevascularlevel,causesaseriesofinflammatoryresponses,collectively
referredtoas“neurogenicinflammation”(GeppettiandHolzer1996).Giventheir
relevanceinmigraine andotherdiseases,neurogenicinflammatoryresponses will
be further discussed in Sects. 5 and 6. The peculiar property of capsaicin, first to
excite and thereafter to desensitize both afferent (nociception) and efferent (neu-
rogenic inflammation) responses, has given an unprecedented contribution to our
currentunderstandingoftheroleoftheseneuronsinhealthanddisease.Inaddition
toTRPV1,peptidergicnociceptorsalsoexpressotherTRPs,includingtheTRPV2,
TRPV3, and TRPV4 channels and TRPA1 (Story et al. 2003), whereas TRPM8
seemstobeconfinedtonon-peptidergicsensoryneurons(Bhattacharyaetal.2008).
Because of the property to sense temperatures from cold (A1 and M8) to warm
(V3andV4)andhot(V1andV2),thesechannelshavebeencollectivelylabelledas
thermoTRPs(Guleretal.2002;Watanabeetal.2002;Storyetal.2003).Exogenous
agents,recognizedearlyonasthermoTRPstimulants,includecamphorforTRPV3
andTRPV4(Moqrichetal.2005),mentholforTRPM8(McKemyetal.2002;Peier
etal.2002),andmustardandcinnamonoilforTRPA1 (Bandelletal.2004;Jordt
etal.2004).Theabilitytosense,inadditiontovariationsintemperature,physical
and chemical changes within nerve terminal milieu indicates thermoTRPs as
molecular integrators of multiple sensory modalities. Finally, coexistence of neu-
ropeptides and TRPs in the same sensory nerve terminals implies that different
channel(TRPV1,TRPV4,orTRPA1)activationmaydrivethereleasemechanism
that eventually results in the protective and/or detrimental process promoted by
neurogenicinflammation(GeppettiandHolzer1996).
2 TRPA1 Channel
From its first cloning (Jaquemar et al. 1999), the ankyrin-1 subtype of the TRP
superfamilyhasgainedincreasingscientificinterestbecauseofitsroleasasensor
ofirritatingandcell-damagingagents.Inparticular,theidentificationofTRPA1as
the target of an unprecedented series of chemically diverse molecules, many of