331 Review www.expert-reviews.com ISSN 1751-2433 © 2010 Expert Reviews Ltd 10.1586/ECP.10.13 Molecular properties Characterization The first molecular identification of acid-sensing ion channels (ASICs) – at that time, known as BNC1, MDEG or BNaC1-2 – was achieved in 1996 and 1997 by Michael Welsh’s, Michel Lazdunski’s and David Corey’s groups [1–3] . However, the essential discovery that these pro- teins form proton-gated channels that could sup- port the proton-activated currents described in the 1980s in neurons [4,5] was made by Michel Lazdunski’s group in 1997 [6] , who called these channels ASICs. They belong to the epithelial Na + channel (ENaC)/DEG/ASIC family of ion channels [7], which comprises ENaC [8,9] involved in taste perception and Na + homeostasis in mam- mals, the neuronal and muscular degenerins of the nematode Caenorhabditis elegans involved in mechanoperception [10–13] and the FMRFamide peptide-gated Na + channel (FaNaC) identified from the invertebrate nervous system [14,15] . The ASIC family in mammals comprises four different genes encoding at least six channel iso- forms (FIGURE 1) . Both ASIC1 and ASIC2 have splice variants, known as ASIC1a (also named ASIC or ASICa or BNaC2a) [3,6] , ASIC1b (also named ASICb or BNaC2b) [16,17] , ASIC2a (also named MDEG1 or BNaC1a or BNC1a) [1–3,18] and ASIC2b (also named MDEG2 or BNaC1b [19] . The ASIC1b isoform has not been described in human so far. One variant of ASIC3 (also named DRASIC or TNaC) [20–23] has been identified in rodents, whereas at least three variants called ASIC3a, b and c (differing in their C-terminal domain) have been reported in humans. ASIC4 (also named SPASIC) [24,25] also has two splice variants in humans, differing only by the deletion of a 19-amino acid region in the extracellular loop. The properties and the physiological relevance of these human splice variants of ASIC3 and ASIC4 remain unclear. Acid-sensing ion channels are assembled in the membrane of neurons as complexes containing accessory proteins, which are important for con- trol of both functional properties and subcellular localization [26–39] . Structure Each ASIC subunit has two hydrophobic trans- membrane regions flanking a large extracellular loop representing more than 50% of the protein, and short intracellular N- and C-termini (FIGURE 1) . Jacques Noël 1 , Miguel Salinas 1 , Anne Baron 1 , Sylvie Diochot 1 , Emmanuel Deval 1 and Eric Lingueglia †1 1 Institut de Pharmacologie Moléculaire et Cellulaire, Institut de NeuroMédecine Moléculaire (IPMC-IN2M) CNRS/ University of Nice-Sophia Antipolis, UMR 6097, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France † Author for correspondence: Tel.: +33 493 953 423 Fax: +33 493 957 708 [email protected] Acid-sensing ion channels (ASICs) form a family of voltage-independent cation channels that predominantly conduct Na + ions, and were identified at the molecular level a little more than a decade ago. ASICs are activated by extracellular acidification within the physiological range, and they form effective proton sensors in both central and peripheral sensory neurons. A combination of genetic and pharmacologic approaches has revealed their implication in an increasing number of physiological and pathophysiological processes – most of them associated with extracellular pH fluctuations, ranging from synaptic plasticity, learning, memory, fear, depression, seizure termination and neuronal degeneration to nociception and mechanosensation. ASICs, therefore, emerge as new potential therapeutic targets in the management of psychiatric disorders, stroke, neurodegenerative diseases and pain. KEYWORDS: acidosis • acid-sensing ion channel • amiloride • brain • chemosensation • dorsal root ganglia • mechanosensation • Na + channels • neurons • pain • protons • synapse Current perspectives on acid‑sensing ion channels: new advances and therapeutic implications Expert Rev. Clin. Pharmacol. 3(3), 331–346 (2010) For reprint orders, please contact [email protected]
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331
Review
www.expert-reviews.com ISSN 1751-2433© 2010 Expert Reviews Ltd10.1586/ECP.10.13
Molecular propertiesCharacterizationThe first molecular identification of acid-sensing ion channels (ASICs) – at that time, known as BNC1, MDEG or BNaC1-2 – was achieved in 1996 and 1997 by Michael Welsh’s, Michel Lazdunski’s and David Corey’s groups [1–3]. However, the essential discovery that these pro-teins form proton-gated channels that could sup-port the proton-activated currents described in the 1980s in neurons [4,5] was made by Michel Lazdunski’s group in 1997 [6], who called these channels ASICs. They belong to the epithelial Na+ channel (ENaC)/DEG/ASIC family of ion channels [7], which comprises ENaC [8,9] involved in taste perception and Na+ homeostasis in mam-mals, the neuronal and muscular degenerins of the nematode Caenorhabditis elegans involved in mechanoperception [10–13] and the FMRFamide peptide-gated Na+ channel (FaNaC) identified from the invertebrate nervous system [14,15].
The ASIC family in mammals comprises four different genes encoding at least six channel iso-forms (Figure 1). Both ASIC1 and ASIC2 have splice variants, known as ASIC1a (also named ASIC or ASICa or BNaC2a) [3,6], ASIC1b
(also named ASICb or BNaC2b) [16,17], ASIC2a (also named MDEG1 or BNaC1a or BNC1a) [1–3,18] and ASIC2b (also named MDEG2 or BNaC1b [19]. The ASIC1b isoform has not been described in human so far. One variant of ASIC3 (also named DRASIC or TNaC) [20–23] has been identified in rodents, whereas at least three variants called ASIC3a, b and c (differing in their C-terminal domain) have been reported in humans. ASIC4 (also named SPASIC) [24,25] also has two splice variants in humans, differing only by the deletion of a 19-amino acid region in the extracellular loop. The properties and the physio logical relevance of these human splice variants of ASIC3 and ASIC4 remain unclear.
Acid-sensing ion channels are assembled in the membrane of neurons as complexes containing accessory proteins, which are important for con-trol of both functional properties and subcellular localization [26–39].
StructureEach ASIC subunit has two hydrophobic trans-membrane regions flanking a large extracellular loop representing more than 50% of the protein, and short intracellular N- and C-termini (Figure 1).
Jacques Noël1, Miguel Salinas1, Anne Baron1, Sylvie Diochot1, Emmanuel Deval1 and Eric Lingueglia†1
1Institut de Pharmacologie Moléculaire et Cellulaire, Institut de NeuroMédecine Moléculaire (IPMC-IN2M) CNRS/ University of Nice-Sophia Antipolis, UMR 6097, 660 Route des Lucioles, Sophia Antipolis, 06560 Valbonne, France†Author for correspondence:Tel.: +33 493 953 423 Fax: +33 493 957 708 [email protected]
Acid-sensing ion channels (ASICs) form a family of voltage-independent cation channels that predominantly conduct Na+ ions, and were identified at the molecular level a little more than a decade ago. ASICs are activated by extracellular acidification within the physiological range, and they form effective proton sensors in both central and peripheral sensory neurons. A combination of genetic and pharmacologic approaches has revealed their implication in an increasing number of physiological and pathophysiological processes – most of them associated with extracellular pH fluctuations, ranging from synaptic plasticity, learning, memory, fear, depression, seizure termination and neuronal degeneration to nociception and mechanosensation. ASICs, therefore, emerge as new potential therapeutic targets in the management of psychiatric disorders, stroke, neurodegenerative diseases and pain.
Keywords: acidosis • acid-sensing ion channel • amiloride • brain • chemosensation • dorsal root ganglia • mechanosensation • Na+ channels • neurons • pain • protons • synapse
Current perspectives on acid‑sensing ion channels: new advances and therapeutic implicationsExpert Rev. Clin. Pharmacol. 3(3), 331–346 (2010)
For reprint orders, please contact [email protected]
Expert Rev. Clin. Pharmacol. 3(3), (2010)332
Review Noël, Salinas, Baron, Diochot, Deval & Lingueglia
ASICs are one of the relatively few ion channels with known atomic-scale structure. The tridimensional structure of chicken ASIC1 was solved by Eric Gouaux’s group in 2007 [40,41]. It shows that three subunits need to assemble together to form a channel (Figure 1). The chalice-shaped homotrimer is composed of short N- and C-termini (whose tridimensional structure has not been elucidated so far), two transmembrane helices, a bound Cl- ion and a disulphide-rich extracellular domain. Each subunit has been compared with a clenched hand, which can be further divided into finger, thumb, palm, knuckle, b-ball, wrist in the extracellular domain, and fore-arm as the pore-forming transmembrane domains TM1 and TM2 (Figure 1) [40].
Biophysical properties & gating Selectivity & conductanceAcid-sensing ion channels are low-conductance, depolarizing channels that predominantly conduct Na+ (gNa ~10–15 pS) [6,19,22]. The rapidly desen-sitizing peak current (Figure 1) is always Na+ selective but the additional sustained cur-rent present in ASIC3-containing channels poorly discriminates between Na+ and K+ in human ASIC3 [21], as well as in rat hetero-meric ASIC3+ASIC2b channels [19]. Protons have also been shown to permeate through ASIC1a, which contributes to rundown (tachyphylaxis) of the channel activity upon successive acid stimulations[42]. ASIC1a is, in addition, permeable to Ca2+ [6,17,43]. Activation of ASIC1a increases intracellu-lar free Ca2+concentration in cortical, hip-pocampal and dorsal root ganglia (DRG) neurons, and in cells expressing the recom-binant channel [44–47]. However, direct per-meation of Ca2+ through ASIC1a seems to contribute only modestly to the intracellular Ca2+ rise in neurons [45,47,48], and much of the increase in free Ca2+ could be mediated by indirect secondary mechanisms.
Activation by extracellular pHThe only known activators of ASICs are extracellular protons. However, the ASIC2b and ASIC4 isoforms are not activated by acidic pH on their own but can associate with other ASICs to modu-late their properties and/or their expres-sion [19,49]. The ASIC subunits can assem-ble as either homo- or hetero-trimeric channels, giving rise to a wide range of currents with different sensitivity to exter-nal H+, kinetics and pharmacology, which accounts for the large diversity of native ASIC-like currents observed in neurons [4]. ASIC channels are not voltage-dependent
and their pH0.5
ranges from 4.0 to 6.8, with activation thresh-olds close to pH 7.0 for ASIC1 and ASIC3 (i.e., well in the pathophysio logical pH range) (Table 1). They show steep pH dependence, making them very sensitive sensors of extracellu-lar protons. A rapid drop of extracellular pH triggers a transient inward current that desensitizes rapidly (within seconds) (Figure
1). Interestingly, the reactivation process of the ASIC1a and ASIC2a channels is strongly pH dependent [50]. Pre-existing pH has a profound effect on the ASIC response, and prolonged or slow acidifi cation of the medium results in inactivation of most of the transient response. However, ASIC3-containing channels have an additional slowly activating, sustained component that does not inactivate, so long as the pH remains acidic [20,22]. ASIC3 is actually capable of adapting three different modes of functioning depending on the pH conditions [51]. In the first mode, a rapid decrease in the pH of the extracellular medium
ASIC1aASIC1b
ASIC2aASIC2b
ASIC3
ASIC4
ASIC1a
5s
pH pH
ASIC3
Loop
Loop
AmilorideA-317567 Na +Ca 2+PcTx1
(ASIC1a)
APETx2(ASIC3)
TM
N C
H+H+
H+
H+
H+
H+
TMTM
Out
In
Finger Knuckle
PalmThumb
Wrist
β-ball
A B
C D
Expert Rev. Clin. Pharmacol. © Future Science Group (2010)
Figure 1. Structure and activity of acid-sensing ion channels. (A) The ASIC family is comprised of at least six members that form proton-activated cation channels (except for ASIC2b and ASIC4) with different properties. A rapid drop in extracellular pH triggers a transient inward current that desensitizes within seconds, but ASIC3 has an additional sustained component that does not inactivate while the pH remains acidic. (B) Each ASIC subunit has two hydrophobic transmembrane regions flanking a large extracellular loop, and three subunits assemble together to form a functional channel that predominantly conducts Na+ ions (and some Ca2+ ions for ASIC1a). (C) Amiloride and A-317567 are nonselective (amiloride), nonsubtype-specific blockers of ASICs, while the spider toxin, PcTx1, selectively inhibits ASIC1a channels, and the sea anemone toxin, APETx2, selectively inhibits ASIC3-containing channels. (D) At the atomic level, each subunit looks like a clenched hand [40,41], and it has been proposed that protons binding to the acidic pocket, palm, and wrist domains in the loop open the channel pore through a rotation of the transmembrane helices. ASIC: Acid-sensing ion channels; TM: Transmembrane.
www.expert-reviews.com 333
ReviewAcid-sensing ion channels: new advances & therapeutic implicationsTa
ble
1. P
rop
erti
es o
f ac
id-s
ensi
ng
ion
ch
ann
els.
Iso
form
Tiss
ue
dis
trib
uti
on
pH
0.5
acti
vati
on
Inh
ibit
ors
End
og
eno
us
mo
du
lato
rsPh
ysio
log
y Po
ten
tial
th
erap
euti
c im
plic
atio
ns
ASI
C1a
Stro
ng e
xpre
ssio
n in
PN
S, b
rain
, spi
nal c
ord,
re
tina.
Als
o pr
esen
t in
ta
ste
cells
, per
iphe
ral
and
cent
ral a
udito
ry
syst
em, i
mm
une
cells
, lu
ng e
pith
elia
l cel
ls,
bon
e, v
ascu
lar
smo
oth
mus
cle
cells
, glio
mas
6.2
–6
.8A
milo
rid
e an
d d
eriv
ativ
es
ben
zam
il an
d EI
PA [6
],
NSA
IDs
(ibup
rofe
n/
flurb
ipro
fen
) [68
],
A-3
1756
7 [6
7],
nafa
mo
stat
mes
ilate
[70]
, di
aryl
amid
ines
[72]
, Pb2
+
[77]
, Ni2
+ [7
6], Z
n2+ [7
8],
Ca2
+ [6
,63]
, psa
lmot
oxin
-1
(PcT
x1) [
82]
RFa
mid
e p
epti
des
[90]
, d
ynor
phin
s [9
8]
arac
hid
onic
ac
id [5
4,14
2],
lact
ate
[158
],
NO
[143
]
Impo
rtan
t ro
le in
the
CN
S: s
ynap
tic t
rans
mis
sion
and
pl
astic
ity,
lear
ning
and
mem
ory
[101
], in
nate
and
co
nditi
oned
fea
r [9
9,10
6], c
hem
osen
sory
fun
ctio
n of
the
am
ygda
la [1
09],
dep
ress
ion
[110
], c
entr
al m
odul
atio
n of
pa
in t
hrou
gh t
he o
pioi
d sy
stem
[149
], c
entr
al
sens
itiza
tion
to p
ain
in t
he s
pina
l cor
d [5
0,13
2], v
isua
l tr
ansd
uctio
n [1
90].
Als
o in
volv
ed in
prim
ary
hype
ralg
esia
in
mus
cle
[152
], v
isce
ral b
ut n
ot c
utan
eous
m
echa
nose
nsat
ion
[137
,163
], p
ossi
ble
impl
icat
ion
in
chem
otra
nsdu
ctio
n of
low
pH
by
caro
tid b
ody
[184
]
Inhi
biti
on: p
sych
iatr
ic
diso
rder
s (a
nxi
ety,
pan
ic,
dep
ress
ion
), s
tro
ke,
neu
rod
egen
erat
ive
dise
ases
, pai
n A
ctiv
atio
n: s
eizu
re
trea
tmen
t
ASI
C1b
PNS,
tas
te c
ells
, co
chle
ar h
air
cells
, ca
roti
d b
od
y,
imm
une
cells
5.1–
6.2
Am
ilori
de
[16]
, di
aryl
amid
ines
[72]
, Pb
2+ [7
7]
NO
[143
]N
oci
cept
ion?
Pain
?
ASI
C2a
PNS
(incl
udin
g sp
ecia
lized
cut
aneo
us
mec
hano
sens
ory
stru
ctur
es),
bra
in,
spin
al c
ord,
ret
ina,
p
erip
hera
l and
cen
tral
au
dito
ry s
yste
m, t
aste
ce
lls, b
one,
vas
cula
r sm
oot
h m
uscl
e ce
lls,
som
e ex
pres
sion
in
caro
tid
bo
dy,
glio
mas
4.1
–5.0
Am
ilori
de
[18]
, naf
amo
stat
m
esila
te [7
0],
diar
ylam
idin
es [7
2],
Cd2
+ [7
6], A
-317
567
[67]
NO
[143
], Z
n2+ [7
9]M
odu
lati
on o
f A
SIC
1a in
the
CN
S [9
5], v
isua
l tr
ansd
ucti
on [1
88],
cut
aneo
us a
nd v
isce
ral
mec
hano
sens
atio
n [1
28,1
63],
no
ise
susc
eptib
ility
of
hear
ing
[193
], b
aror
ecep
tor
refl
ex [1
83],
may
be
invo
lved
in
sou
r ta
ste
per
cept
ion
[197
,198
], v
ascu
lar
smo
oth
mus
cle
cell
mig
rati
on [2
11]
Con
tro
l of
blo
od
pres
sure
, pai
n?
Not
e g
enet
ic
asso
ciat
ions
wit
h m
ultip
le s
cler
osi
s, a
utis
m
and
men
tal r
etar
dati
on
ASI
C2b
PNS,
bra
in, s
pina
l cor
d,
retin
a, t
aste
cel
lsN
AN
AM
odu
late
the
pro
per
ties
of
othe
r A
SIC
s (m
ainl
y A
SIC
2a a
nd A
SIC
3) [
19,2
9]Pa
in?
ASI
C3
PNS
(incl
udin
g sp
ecia
lized
cut
aneo
us
mec
hano
sens
ory
stru
ctur
es),
ret
ina,
ta
ste
cells
, car
otid
b
od
y, in
ner
ear
, tes
tis,
bon
e, lu
ng e
pith
elia
l ce
lls, v
ascu
lar
smo
oth
mus
cle
cells
6.2
–6
.7A
milo
rid
e [2
2], N
SAID
s (a
spiri
n/d
iclo
fena
c) [6
8],
A-3
1756
7 [6
7],
nafa
mo
stat
mes
ilate
[70]
, di
aryl
amid
ines
[72]
, G
d3+ [7
4], C
d2+ [7
6], P
b2+
[77]
, APE
Tx2
[85]
RFa
mid
e p
epti
des
[52,
90],
ar
achi
don
ic a
cid
[54,
142]
, lac
tate
[1
58],
NO
[143
],
hyp
erto
nici
ty [5
4]
Car
diac
pai
n [4
3],
cuta
neo
us a
cidi
c an
d pr
imar
y in
flam
mat
ory
pain
[54]
, sec
onda
ry m
echa
nica
l hy
per
alg
esia
in m
uscl
e an
d jo
ints
[153
,155
], c
utan
eous
an
d vi
scer
al m
echa
nose
nsat
ion
and
mec
hano
-no
cice
ptio
n [1
26,1
63,1
65],
aci
d se
nsin
g in
ga
stro
eso
phag
eal a
ffer
ents
[161
], m
aint
enan
ce o
f re
tinal
inte
grit
y [1
91],
hea
ring
[192
], t
esto
ster
one
hom
eost
asis
[156
], p
oss
ible
impl
icat
ion
in
chem
otra
nsdu
ctio
n of
low
pH
by
caro
tid
bo
dy
[184
] an
d lo
cal v
ascu
lar
cont
rol i
n m
uscl
e [1
86]
Inhi
biti
on: i
nflam
mat
ion
-re
late
d pa
in, c
hron
ic
mus
cula
r pa
in, a
ngin
a,
arth
ritis
, gas
trit
is,
infla
mm
ator
y an
d no
ninfl
amm
ator
y b
owel
dis
ord
ers
ASI
C4
PNS
(low
exp
ress
ion
),
brai
n, s
pina
l cor
d,
pitu
itar
y gl
and,
ret
ina,
in
ner
ear
, im
mun
e ce
lls
NA
??
May
mo
dula
te t
he p
rop
erti
es o
f ot
her
ASI
Cs
[49]
?
ASI
C: A
cid
-sen
sin
g io
n ch
ann
els;
NA
: Not
ap
plic
able
; PN
S: P
erip
her
al n
ervo
us
syst
em.
Expert Rev. Clin. Pharmacol. 3(3), (2010)334
Review Noël, Salinas, Baron, Diochot, Deval & Lingueglia
generates a fast transient current, which, by itself, is large enough to depolarize the membrane and trigger action potentials [52]. In the second mode, sustained and modest acidifications of the extracellular medium (between pH 7.3 and 6.7 in rat isoform), which all remain near the physiological pH, generate a window current, due to the overlap between inactivation and activation of the channel, which produces persistent depolarization [53,54]. In the third mode, more severe sustained acidifications (pH <6.0) activate a plateau current through a specific mechanism, also producing a persistent depolarization [51].
Proton sensing & gatingBased on the 3D structure [40,41], hypotheses have been developed to describe proton sensing and gating of ASIC channels. Several regions have been involved in pH sensing. A cluster of acidic amino acids in the extracellular domain forms an ‘acidic pocket’ with carboxyl–carboxylate pairs [40]. This putative pH sensor may associate binding of protons and opening of the channel via the TM1 domain [40,55]. Another ‘proton-sensitivity signature’ is present in a second region located at the base of the palm domain [56]. Protonation of amino acids that form a ring of negative charges around the outer entrance of the channel in a third region in the wrist domain are probably also necessary for gating [57]. The global conformational change induced by protons binding to the acidic pocket, palm and wrist domains, could open the channel pore through a rotation of the transmembrane helices [40,41,58,59], releasing a constriction formed by the crossing of TM2 domains that occludes the ion conduction pathway (Figure 1) [41]. Na+ ions may access the pore either through three oval-shaped fenestra-tions located at the base of the extracellular domain near the junction with transmembrane domains [40], and by a path along the threefold axis of symmetry in the extracellular domain [41]. Displacement during acidification of the Ca2+ ions bound to the channel in the closed state also seems to be an important feature of ASIC gating [40,57,60–62]. Interestingly, ASICs are regulated by extracellular Ca2+ with a dual inhibitory and stimulatory effect [6,43,57,63–65]. The cytosolic domains, for which the 3D structure is not known, have also been involved in the regulation of channel gating [42,51,66] but the mechanisms remain poorly characterized.
Pharmacology Small molecules & metal ionsAmiloride, a K+-sparing diuretic, is a weak, nonselective inhibitor of ASIC channels in the micromolar concentration range that acts as a pore blocker. Amiloride has an additional paradoxical -enhancing effect on the sustained current component of ASIC3 [22,53]. Amiloride derivatives, benzamil and EIPA, are also reversible, poorly selective blockers of ASIC channels. The ami-dine A-317567 has been described as a more specific inhibitor of ASICs, with IC
50 between 2 and 30 µM on native ASIC currents
in DRG neurons [67]. A-317567 was shown to be more potent than amiloride in vitro and in vivo in models of inflammatory and postoperative pain in rats [67]. ASIC1a and ASIC3 are also directly inhibited by therapeutic concentrations of NSAIDs (IC
50
~92–350 µM) [68,69], and the clinically used protease inhibitor,
nafamostat mesilate, reversibly blocks recombinant human ASIC1a, ASIC2a and ASIC3 channels expressed in Xenopus oocytes (IC
50 ~2.5–71 µM) [70]. The aminoglycosides streptomy-
cin and neomycin partially and reversibly inhibit ASIC currents in DRG neurons (IC
50 ~32–44 µM) [71]. Diarylamidines (e.g.,
DAPI, diminazene, hydroxystilbamidine and pentamidine) have recently been shown to inhibit ASIC currents in primary culture of hippocampal neurons (IC
50 ~2.8, 0.3, 1.5 and 38 µM, respec-
tively), and diminazene reversibly blocks recombinant ASIC1a, ASIC1b, ASIC2a and ASIC3 channels expressed in Chinese ham-ster ovary (CHO) cells [72]. ASIC channels are inhibited by a vari-ety of heavy-metal ions (Gd3+, Pb2+, Ni2+, Cd2+ and Cu2+) [73–77] and bivalent cations (Ca2+ and Zn2+) [6,63,78]. Extracellular Zn2+ at micromolar concentrations also potentiates the acid activation of homomeric and heteromeric ASIC2a-containing channels [79], and the native ASIC currents in rat hippocampal neurons [80].
Peptide toxinsTwo toxins that selectively and efficiently block ASICs in vitro and in vivo in a subtype-specific manner have been isolated from animal venoms [81]. The spider toxin, Psalmotoxin 1 (PcTx1), blocks ASIC1a homomeric channel with an IC
50 of approximately
0.9 nM [82–84]. The sea anemone toxin, APETx2, blocks homo-meric ASIC3 with an IC
50 of approximately 63 nM, as well as
ASIC3-containing heteromeric channels (IC50
~0.1–2 µM) [85,86]. PcTx1 is a gating modifier that binds with the highest affinity to the desensitized state of the channel at a site in the extracel-lular domain close to the acidic pocket [83,87,88]. The toxin causes both a robust shift of the steady-state desensitization curve and a shift of the proton-activation curve to higher pH. The resulting increase of the affinity for protons inhibits ASIC1a by shifting most channels into the desensitized state at pH 7.4 [87]. PcTx1 also interacts with ASIC1b, and the toxin binds to the open state and does not inhibit the channel but promotes its opening at slight acidification [89].
NeuropeptidesFMRFamide and structurally related peptides, such as FRRFamide and neuropeptide FF (NPFF, FLFQPQRFamide) potentiate H+-gated currents of heterologously expressed ASIC1 and ASIC3, but not ASIC2a (EC
50 ~10–50 µM; threshold
~1 µM) [52,90–92]. The neuropeptides increase the peak ampli-tude and/or slow inactivation of the H+-gated current, which induces or increases the sustained phase during acidification. The peptide effect seems to be by direct binding on the chan-nel [52,90,93]. The peptides alter steady-state desensitization of ASIC1a [94]. ASIC2a is capable of increasing the response to peptides in heteromeric channels containing ASIC1a or ASIC3 subunits [91,95]. The modulation of ASICs by RFamide-related neuropeptides is strongly pH dependent (half-maximal effect achieved at pH 5.6–6.0 [96]) and requires FMRFamide addition at pH 7.4 (i.e., when the channel is closed) [90]. Knockout mice have demonstrated the major role of ASIC3 in mediating the sensory response to FMRFamide and FRRFamide [93,97]. The ASIC1 contribution to the effect seems to be very modest [93,97],
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which is consistent with the lower potency of FMRFamide and related peptides in modulating ASIC1a compared with ASIC3. Two endogeneous opioid neuropeptides, dynorphin A and big dynorphin, have recently been shown to directly interact with ASIC1a and enhance channel activity by preventing its steady-state desensitization [98].
ASICs in the brain Native ASIC-like currents have been reported in almost all types of brain neurons. In rodents, ASIC1a and ASIC2, but not ASIC3, are widely distributed in the cortex, striatum, hip-pocampus, olfactory bulb, amygdala and cerebellum [99,100]. ASIC1 and ASIC2 are detected in brain synaptosomal fractions, suggesting a synaptic localization [33,101,102]. Genetic deletion of ASIC1 eliminates the H+-evoked currents in hippocampal [95,101] and amygdala neurons [99], which illustrates the central importance of this isoform in the brain. ASIC channels in the brain have been largely studied with ASIC1-knockout mice, revealing physiological and pathophysiological roles in different brain regions (Figure 2).
ASICs in the hippocampus: dendrite morphology, synaptic plasticity, learning & memoryFunctional ASIC channels have been detected in cultured hippo campal neurons [80,101,103]. The important function of ASIC1 in the hippocampus is demonstrated in ASIC1-knockout mice, which show impaired hippocampal long-term potentia-tion and defects in spatial learning and memory [101]. In hip-pocampal neurons, ASIC1a and ASIC2a are present in the postsynaptic membrane of the dendritic tree and dendritic spines [27,33,101]. The presence of ASIC2a increases the density of ASIC1a in spines through an association with the PDZ-containing protein PSD-95 [33]. It has been proposed that the secondary increase in intracellular Ca2+ mediated by ASIC1a positively affects the spine density in hippocampal neurons through the Ca2+-mediated CaMKII signaling pathway [48]. However, ASIC1-knockout mice do not have reduced spine density [48]. The contribution of ASIC1a to the presynaptic function is not clear since paired pulse facilitation (an index of presynaptic activity and neurotransmitter-release probability) is normal in hippocampal slices from ASIC1-knockout mice [101], but a recent study has shown an increase of the probability of neuro- transmitter release in cultured hippocampal neurons from the same knockout mice [104].
ASIC1a in amygdala: fear, chemosensing & depressionExpression of ASIC1a is particularly high in the amygdala, a brain region involved in fear, arousal and emotions [99]. In this structure, ASIC1a seems to contribute to fear responses to a variety of aversive stimuli, perhaps, in part, through a contribution to synaptic plastic-ity underlying the acquisition of conditioned fear [101,105]. ASIC1-knockout mice show impaired fear conditioning [99] and innate fear [106], and restoring ASIC1a expression in the basolateral amy-gdala of knockout mice rescues contextual fear conditioning [107]. Conversely, overexpression of ASIC1a in transgenic mice increases
fear conditioning [108]. Recently, ASIC1a has been shown to act in the amygdala as a pH sensor that contributes to the production of fear behavior associated with the inhalation of CO
2 and acidosis [109].
Loss of ASIC1 in knockout mice or pharmacological inhi-bition of homomeric ASIC1a channels by the PcTx1 toxin, or of ASIC channels by A-317567, generates antidepressant effects [110]. Restoring ASIC1a in the amygdala with a viral vector eliminates the antidepressant-like phenotype in ASIC1a-knockout mice, suggesting that the amygdala plays a key role in the anti-depressant-like effects associated with ASIC1a deletion or inhibition [110].
ASIC1a & neurodegeneration Activation of ASIC1a during the metabolic acidosis accompanying experimental stroke has been proposed to contribute to neuronal death associated with brain ischemia [38,46]. ASIC1a has also been proposed to contribute to axonal degeneration in autoimmune inflammation of the CNS in a mouse model of multiple scle-rosis, where significant tissue acidosis occurs [111]. Interestingly, amiloride and, to a lesser extent, spider venom containing the PcTx1 toxin, are neuroprotective in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease [112]. Amiloride and benzamil also improve pathological changes in cellular and animal models of Huntington’s disease [113], and amiloride reduces hippocampal neuronal degeneration following traumatic brain injury in rats [114].
ASIC1a & seizure It has long been known that breathing carbon dioxide makes brain tissue more acidic and stops seizures, and seizures them-selves are known to reduce brain pH. The anti-epileptic effect of low pH has been ascribed to an increase in the inhibitory tone of inhibitory interneurons through ASIC1a activation [115]. Interestingly, ASIC currents have been reported to be stronger in inter neurons than in excitatory neurons [116]. ASIC1a activa-tion can, therefore, have an inhibitory effect and a protective function in the brain. Whether ASIC channels are protective or deleterious may depend on the location of ASIC activation, the magnitude and duration of acidosis, and the presence of modulators of ASIC function [115]. Several recent studies also have shown an amiloride inhibition of seizures in rats and mice [117–119], raising the additional possibility of some contribution of ASICs to the generation of seizure.
Roles at the synapseThe localization of ASIC1a and the phenotype of knockout mice suggest a role at the synapse. A proton pump acidifies synaptic vesi-cles [120] and provides the electrochemical gradient for transmitter uptake. When vesicles fuse with the plasma membrane, protons are released along with neurotransmitters into the synaptic cleft, which may modulate synaptic transmission. In mammalian cone photoreceptor ribbon synapses, discharged protons can affect the presynaptic Ca2+ channel and vesicle release [121,122]. Similarly, H+ released in the cleft might activate synaptic ASICs in conven-tional synapses. This post synaptic ASIC-generated depolarization
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TongueSour taste (ASIC2a)
JointsSecondary mechanical hyperalgesia (ASIC3)
BrainSynaptic transmission and plasticityLearning and memoryInnate and conditioned fearChemosensing of the amygdala (ASIC1a)
Gastrointestinal tractAcid sensing (ASIC3)Mechanosensation (ASIC1, 2 and 3)Mechano-nociception (ASIC3)
Auditory systemHearing (ASIC3)Noise susceptibility (ASIC2a)
Carotid bodyChemosensation (ASIC1 and/or 3)
Heart and aortic archCardiac pain (ASIC3)Baroreceptor reflex (ASIC2a)
RetinaVisual transduction (ASIC1a, 2a and 3)Maintenance of retinal integrity (ASIC3)
MusclePrimary hyperalgesia (ASIC1a)Secondary mechanical hyperalgesia (ASIC3)Local vascular control (ASIC3)
SkinAcidic and primary inflammatory pain (ASIC3)Mechanosensation (ASIC2a and 3)
Spinal cordCentral sensitization and modulation of pain (ASIC1a)
Noël, Salinas, Baron, Diochot, Deval & Lingueglia
has been proposed to facilitate the release of the Mg2+ block of the NMDA receptor, and contributes to synaptic plasticity [101]. However, ASIC-mediated postsynaptic currents have not been detected during synaptic transmission [101,102,104,123], and the extent of the synaptic pH changes and whether or not these changes are sufficient to activate ASIC1a, remains to be determined. In addition, and as mentioned earlier, it is conceivable that ASIC1a could also contribute to the presynaptic function. Interestingly, it was recently demonstrated that protons can serve as intercellular transmitters
between intestinal cells and defecation muscles in C. elegans [124].
ASICs & nociceptionAcid-sensing ion channels are present in primary sensory neurons of the trigeminal, vagal and dorsal root ganglia. ASIC1, ASIC2 and ASIC3 are expressed in small and medium neurons (i.e., the nociceptive neurons that are able to detect noxious stimuli) [68,125–130]. ASIC2 and ASIC3 have also been found in large non-nociceptive neurons that mostly correspond to low-threshold mechanoreceptors. The proteins have been detected in the soma and in the peripheral nerve endings of DRG neurons [125–128]. The presence of ASICs on central projections in the dorsal horn of the spinal cord is less clear [125,131,132]. ASICs support most of the native proton-activated cation currents in sensory neurons, although a significant part of the sustained response to low pH can be attributed to the capsaicin receptor TRPV1 [133]. The native ASIC-like responses are approximately tenfold more sensitive to changes in H+ than the TRPV1 responses.
In rats, activation of nociceptive C-fibers by acid is inhibited by amiloride [134], and ASIC-mediated depolarization of sensory neurons triggers action potentials upon extracellular acidifi-cation [52,135]. ASIC3 is a remarkable subunit because, in addition to its large expression in sensory neurons and steep sensitivity to protons, it can adjust its response to a wide range of extra cellular pH variations by generating transient and sustained currents with a significant impact on the neuronal excitability. As previously described, ASIC3 has three distinct modes of pH sensing. The two persistent modes of activity might explain how ASIC3 underlies a sustained sensation of pain triggered by modest acidifications near the physiological pH (between 7.4 and 6.5) or by more severe decreases in pH, even if its fast transient current component inac-tivates rapidly [53,54]. Therefore, ASICs have been proposed to be sensors of acidic pH on the peripheral terminals of primary sensory neurons and to participate in the perception of pain that accompa-nies tissue acidosis in conditions such as ischemia, inflammation, tumors, infections, lesions or traumatic injuries. Several factors may participate in the drop of extra cellular pH associated with these conditions, such as release of the acidic content of lyzed cells, degranulation of mast cells, organic acids released by metabolism or infectious agents, such as lactic acid released by ischemic muscle and heart, as well as damage to the mucosal barrier of the GI tract or damage to the urinary tract epithelium, exposing the underlying tissue to gastric acid and acidic urine, respectively.
ASICs in somatic painASICs in cutaneous painThe role of ASICs in cutaneous nociception has remained con-troversial until recently because of the apparent lack of phenotype and the conflicting results generated from studies of knockout mice for ASIC1, ASIC2 and ASIC3 [126,136,137] and from a study of ASIC3 dominant-negative mice [138]. For instance, normal, decreased or increased pain behaviors were reported for ASIC3-knockout or -transgenic mice in various studies and different pain models [126,136–138]. However, peripheral injections of the APETx2 toxin (a specific blocker of ASIC3) and knockdown of ASIC3 by
Figure 2. Proposed physiological functions of the different acid-sensing ion channels. ASIC: Acid-sensing ion channels
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intrathecal injections of siRNAs have clearly demonstrated in rat the essential role played by ASIC3 as a sensor of acidic pain, as well as an integrator of molecular signals produced during inflam-mation, where it contributes to primary thermal hyper algesia [54]. Consistent with these data, local peripheral inhibition of ASICs by amiloride and benzamil reduces cutaneous inflammatory pain in rats [139]. This is in agreement with the increased expression of ASICs in rat DRG neurons induced by chronic inflammation of the hind paw [68,135,140,141]. The increase in expression, together with the upregulation of ASIC3 activity by several components of the ‘inflammatory soup’, such as bradykinin, 5-hydroxytryp-tamine [29], hypertonicity [54], arachidonic acid [54,73,142] and nitric oxide [143], may be important for the sensitization of cutaneous nociceptors during inflammation. Interestingly, and consistent with the data in rats, a decrease in pH in the skin of human volunteers has been associated with nonadapting pain [144], and this cutaneous acid-induced pain appears to be largely mediated by ASIC channels, especially at moderate pH (>6.0) [145–147]. A recent study in ASIC3-knockout mice has looked at the nocic-eptive behaviors in both the acute (a few hours) and subacute (1–2 days) phases of inflammation, and reveals an involvement of ASIC3 in the maintenance of primary hyperalgesia (i.e., the increased response to noxious stimuli at the site of injury) in the subacute but not the acute phase [148]. Behavioral responses to cutaneous mechanical and thermal stimuli are unaffected in ASIC1-knockout mice [137], and subcutaneous injections of the PcTx1 toxin in wild-type animals to specifically block homomeric ASIC1a channels have no effect in acute pain models [149], or in a model of inflammatory pain in rats [132]. Consequently, homo-meric ASIC1a channels do not seem to significantly contribute to acute or inflammatory pain at the periphery. However, one cannot exclude a role for ASIC1a in peripheral nociceptor terminals when associated with other ASIC subunits in heteromeric channels.
The contrasting results found in mice and rats could seem sur-prising but may be explained by compensatory mechanisms in knockout animals and/or by species differences in expression of ASIC channels. Indeed, approximately 65% of rat nociceptors innervating the skin express ASIC currents [54], and transient proton-induced ASIC-like currents are less frequent and have smaller current density in the mouse [150].
ASICs in muscle & deep somatic pain Acid-sensing ion channels are expressed in sensory neurons that innervate muscle, joints and bone. ASIC3 is expressed in more than 50% of small muscle afferents in rats [129] and in more than 30% of DRG neurons innervating the knee joint in mice [151]. ASIC expression in DRG is increased in mouse models of mus-cle inflammation [152] and acute arthritis [151]. ASIC3 plays an important role in the generation of secondary mechanical hyper-algesia (i.e., the increased response to noxious stimuli outside the site of injury) and central sensitization achieved in a mouse model of noninflammatory muscular pain induced by repeated acid injections into the muscle [126,153]. ASIC3 is also involved in the development of cutaneous mechanical, but not heat, hyper-algesia induced by muscle inflammation [154]. Conversely, ASIC1
does not participate in acid- or inflammation-induced secondary mechanical hyperalgesia in mouse muscle [152,153], but contributes to primary hyperalgesia in muscle inflammation [152].
Acid-sensing ion channels3 has also been involved in the sec-ondary, but not the primary, mechanical hyperalgesia produced by joint inflammation in mice [155]. Enhanced muscle fatigue also occurs in ASIC3-knockout mice, but only in males, which may be related to lower plasma levels of testosterone [156].
ASICs in visceral pain & mechanosensationAcid-sensing ion channels 3 in cardiac afferents has been pro-posed to be the major detector of myocardial acidity that trig-gers angina during cardiac ischemia [43,157]. Interestingly, organic compounds released during ischemic situations in the heart, but also in muscle and the brain, such as lactate and arachidonic acid, are able to increase ASIC currents in sensory and central neurons [54,73,142,158].
Acid-sensing ion channels transduce acid sensation in gastric sensory nerve endings. ASIC-like currents have been recorded in sensory neurons that innervate the stomach from both dorsal root ganglia and nodose ganglia, and these currents are sensitized by gastric ulceration [159]. ASIC3 has been proposed to contribute to acid sensation in gastroesophageal afferents [160]. ASIC3 does not seem to participate to the acid sensing of vagal afferent neurons in the normal stomach but plays a major role in the increased response to acid associated with experimental gastritis [161]. ASIC3 could, therefore, be important in acid-related, inflammation and ischemia-induced disturbances of gut function and sensation [162], as well as in dyspepsia and GI reflux disease affecting the proximal gastrointesti-nal tract. On the other hand, ASIC2-knockout mice have increased acid-evoked afferent input from the stomach to the brain stem [161].
In addition, ASICs play a role in gastrointestinal mechano-sensory function. Mice lacking ASIC1, 2 and 3 demonstrate altered colonic mechanosensory function. Disruption of ASIC1a increases the mechanical sensitivity in all colonic and gastro-esophageal sensory afferents [137]. Disruption of ASIC2 has mixed effects, while in ASIC3-knockout mice, all afferent classes except gastro esophageal mucosal afferents have markedly reduced mech-anosensitivity [160,163]. Quantitive PCR of laser-captured neurons has identified ASIC3 as the most abundant ASIC transcript in colonic DRG neurons [164], consistent with its contribution to the perception of noxious mechanical stimuli in the mouse colon [165]. ASIC3 is also required for the sensitization (but not the activation) by the acidic inflammatory soup of colon afferent fibers to stretch [165]. It is important to mention that mechanical hypersensitiv-ity of the colon underlies, in part, the chronic abdominal pain experienced by many patients with bowel disorders. Increased ASIC3 expression has been detected in the colonic mucosa of patients with Crohn’s disease (an inflammatory bowel disease) [140], and ASIC3 contributes to the visceral nociceptive behavior in a mouse model of noninflammatory bowel disorder, mimicking the pathophysio logy of irritable bowel syndrome [166].
Acid-sensing ion channel-like currents have been recorded on rat vagal pulmonary sensory neurons [167], and ASIC3 is expressed in rat vagal and glossopharyngeal sensory ganglia [168], as well as in
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spinal afferent neurons projecting to the rat lung and pleura [169]. ASICs have been proposed to play a role in the effect of acidosis on airway basal tone and responsiveness in the guinea pig. [170]. ASICs could, therefore, participate in the response to airway acidification, such as cough and bronchoconstriction [171–173], which are associ-ated with both physiological (e.g., exercise) and pathophysiological (e.g., chronic obstructive pulmonary disease) conditions.
Central ASIC1a & pain modulationAcid-sensing ion channels 1a and ASIC2 are largely expressed in spinal second-order sensory neurons that receive primary afferent inputs. Their expression is upregulated during peripheral inflam-mation, and they may play a role in the processing of noxious stimuli and in the generation of hyperalgesia and allodynia in persistent pain [50,132,174]. Recently, ASIC1a has been involved in central sensitization associated with prolonged pain [132]. FMRFamide-related peptides, which directly modulate ASIC1- and ASIC3-containing channels, are also increased in the spinal cord during chronic inflammation [175–177], which could modulate the response to noxious acidosis. ASIC1-knockout mice do not exhibit sensory deficits [99,101]. However, a role for central ASIC1a in the pain pathway has been clearly demonstrated by intrathecal and intracerebroventricular injections of the PcTx1 toxin in mice and rats, which have a potent analgesic effect in several models of acute and chronic pain [149]. Knockdown of the channel after intrathecal injection of antisense oligonucleotides has a similar analgesic effect. Blocking of the ASIC1a homomeric channels at the spinal and/or supraspinal level results in an activation of the endogenous enkephalin pathway and in increased levels of Met-enkephalin in the cerebrospinal fluid [149], producing strong analgesic effects.
ASICs & other sensory modalities ASICs & mechanotransductionAcid-sensing ion channels are expressed in small DRG neurons, including high-threshold mechanoreceptors, and ASIC2a and ASIC3 are also expressed, as mentioned earlier, in large DRG neu-rons that comprise low-threshold mechanoreceptors. The ASIC2 and ASIC3 proteins have been detected in specialized cutaneous mechanosensory structures, such as Meissner corpuscles, Merkel nerve endings and palisades of lanceolate nerve endings surround-ing the hair shaft [125,126,128]. Interestingly, genetic dissection of mechanosensory transduction in C. elegans have identified mem-bers of the ENaC/DEG/ASIC family of ion channels (i.e., the degenerin MEC-4 and MEC-10), as mechanotransducers in body touch neurons [10–13,178–180]. Thus, ASICs appear to be good can-didates for mechanosensitive ion channels in mammals. However, genetic studies in mice only partially support a role in cutaneous mechanotransduction. Some studies of knockout mice for ASIC2 or ASIC3, but not ASIC1, have reported subtle alterations in cuta-neous mechanical sensitivity (slight increase or slight decrease, depending on the modality tested and the genetic background) [126,128,137,181], while other studies have failed to confirm such a role [103,182]. Very recently, ASIC2 has been detected in the soma and sensory endings of nodose ganglia aortic baroreceptor neurons,
and knockout mice show an impaired baroreceptor reflex, sug-gesting a role for ASIC2, maybe as a pressure sensor, in barorecep-tor sensitivity and neural control of blood pressure [183]. ASIC1, ASIC2 and ASIC3 also differentially contribute to gastrointesti-nal mechanosensory function. Available data so far do not actually support a direct role for ASICs as mechanically gated channels, and their participation in mechanotransduction is more likely to be indirect.
ASICs & chemotransductionAcid-sensing ion channels 1 and ASIC3 are expressed in rat carotid body, and extracellular acidosis evokes ASIC-like inward current in glomus cells – the chemosensitive cells that monitor arterial blood oxygen, carbon dioxide, and pH to regulate breathing – suggesting a contribution of ASIC channels to the detection of low blood pH by the carotid body [184].
A role for ASIC channels in the local vascular control has also been proposed [123]. ASIC3-expressing sensory nerve endings have been shown to innervate muscle arterioles [129]. These afferents may correspond to muscle metaboreceptors that detect changes in muscle metabolism, consistent with the contribution of ASICs to the exercise pressor reflex evoked by metabolic but not mechanical signals generated by contracting skeletal muscle [185,186].
ASICs in vision, hearing & tasteMost ASICs have been detected in rodent retina [187–191]. ASIC2 is a negative modulator of rod phototransduction [188], while ASIC1a is a positive modulator of cone phototransduction and adapta-tion [190]. Inactivation of the ASIC2 gene in the mouse also sen-sitizes the retina toward light-induced degeneration [188]. ASIC3 is also expressed in the rod inner segment of photoreceptors, in horizontal cells, in some amacrine cells and in retinal ganglion cells. Inactivation of ASIC3 enhances visual transduction in mice 2–3 months of age but induces late-onset rod photorecep-tor degeneration and death in older mice, suggesting an important role of ASIC3 in the maintenance of retinal integrity [191].
Acid-sensing ion channels 1, 2 and 3 are expressed in the peripheral auditory system [192–194], and currents corresponding to homomeric ASIC1a- and ASIC2a-containing channels, but not ASIC3 channels, have been recorded in the inferior colliculus of the central auditory system [195]. ASIC2 and ASIC3 are mainly expressed in spiral ganglion neurons of the adult cochlea, which transmit primary acoustic information from cochlear hair cells to the brain. ASIC2-mutant mice show no hearing loss [103,193] but have altered noise susceptibility [193]. ASIC3-knockout mice have normal hearing at 2 months, but develop progressive hearing loss with age [192]. Interestingly, ASIC3-dependent hearing loss in mothers leads to inadequate maternal response to pups’ calls, affecting the social development of pups in adolescence [196].
Several ASICs have been localized to taste buds, with some species-specific expression [197–201]. ASIC2-knockout mice have no significant impairment of responses to sour stimuli [199], but a recent study with two patients unresponsive to sour stimuli but not to other taste modalities, suggests an implication of ASIC channels in sour-taste perception in the human tongue [202].
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Other roles for ASICsAcid-sensing ion channels have been detected in the testis (hASIC3; note that ASIC3-knockout males display lower plasma levels of testosterone [156]) [20,23], pituitary gland (ASIC4) [25], lung epithelial cells (ASIC1a and 3) [203,204], immune cells (ASIC1, 3 and 4) [111], urothelial cells [205], adipose cells (ASIC3) [206] and bone (ASIC1–3) [207,208]. In non-neuronal joint cells, ASIC3 regu-lates pH responsiveness and controls release of the extracellular matrix polysaccharide hyaluronan [209].
Acid-sensing ion channels are expressed in vascular smooth muscle cells (ASIC1–3) [210–213], and ASIC2 has been involved in vascular smooth muscle cell migration [211]. ASIC2-knockout mice also have defects in pressure-induced vasoconstriction in mouse middle-cerebral arteries [213]. A role for ASIC2 in migration of glioma cells has also been proposed [214].
Genetic associations with pathologiesNo inherited human disease caused by mutations in ASICs has been identified so far. However, recent studies suggest genetic associations between the ASIC2 locus and multiple sclerosis, autism and mental retardation [215–217], and a possible link, although marginally significant, between the ASIC1 gene and major depression [218].
Expert commentaryAcid-sensing ion channels constitute a relatively recently iden-tified family of excitatory depolarizing cation channels. Their only known activators are extracellular protons, with a very strong dependence on pH. The structure and function of these channels remain partially understood, but an important step forward came from the recent determination of the 3D struc-ture of chicken ASIC1, showing trimeric organization. ASICs are broadly expressed in the nervous system, both in central and sensory neurons. Available data suggest an essential role for the ASIC1a and ASIC3 isoforms in the central and the periph-eral nervous system, respectively. Nonsubtype-specific inhibi-tors of ASICs are available, such as the nonselective, clinically used diuretic amiloride and A-317567, another small molecule experimentally developed by Abbott Laboratories (UK), which appears to be more selective than amiloride but also exhibits relatively low potency. In addition to these nonselective and/or nondiscriminative inhibitors, more potent and subtype-selective blockers are available, such as a spider peptide toxin (PcTx1) and a sea anemone peptide toxin (APETx2), which specifically block the ASIC1a- and ASIC3-containing channels, respectively. Use of these pharmacological inhibitors has shown, in association with genetic studies using knockout mice of various isoforms, a clear implication of ASICs in brain physiology and patho-physiology, as well as in pain perception and modulation. Of particular interest is the role of ASIC1a in the amygdala, where it contributes to innate and acquired fear, chemosensing of carbon dioxide and depression, making inhibitors of this channel new potential pharmaceutical tools in the management of psychiat-ric disorders, including anxiety, panic and depression. ASIC1a could also represent an interesting target to reduce neuronal
degeneration associated with brain acidosis in stroke and neu-rodegenerative diseases. On the other hand, ASIC1a activators could be beneficial in modulating seizure termination. Central inhibitors of ASIC1a could also offer a new potential line of treatment for chronic pain through positive modulation of the endogenous opioid system. ASIC3 also emerges as a promis-ing target for treatment of persistent somatic and visceral pain, including inflammation-related pain, chronic muscular pain, angina, arthritis, gastritis and inflammatory and noninflam-matory bowel disorders. Finally, implication of ASIC channels in retinal function, carotid body chemotransduction, baro-receptor reflex, hearing, sour-taste perception, and probably in other functions yet to be identified, may also lead to interesting therapeutical applications and must be taken into consideration in any ASIC therapy protocol to minimize adverse side effects.
Five-year viewProtons are the only known activators of ASICs and it is rea-sonable to assume that ASIC functions are supported by their capacity to behave as extracellular pH sensors. However, the possibility of the existence of other stimuli, such as neuro-peptides, cannot currently be ruled out, and some of the func-tions assigned to ASICs may be unrelated to the detection of extracellular pH.
Acid-sensing ion channels are almost ubiquitous in mam-malian CNS neurons. They have been implicated in a number of physiological and pathophysiological conditions but basic knowledge of their contribution to neuronal function remains limited. For instance, the interesting possibility of a signaling role for protons at the synapse via ASICs definitely requires further investigation. Little is also known about the amplitude of pH fluctuations in the brain during normal physiological processes, as well as in pathological situations. Similarly, it is necessary to extend our knowledge of the implication of ASICs in pain, as well as the precise mechanisms of action underlying their roles in nociception, to develop effective therapeutical strategies involving these channels. In this respect, progress in our knowledge of the 3D structure and further exploration of the molecular dynamics of ASICs will greatly facilitate the dis-covery and optimization of new clinically relevant drugs target-ing these channels. Little is still known about ASIC regulation, and there is a need for further investigation in this area, con-sidering the participation of these channels in highly regulated processes in the central and peripheral nervous systems. The molecular basis of the implication of ASICs in mechanosensory function remains largely unknown. It is important to determine if, in certain cellular contexts for instance, some ASICs could be able to transduce mechanical signals, perhaps with the help of accessory proteins present on both side of the plasma membrane, as shown for the related mechanosensitive degenerin channels in C. elegans.
Acid-sensing ion channels are broadly expressed in the nerv-ous system, but there is emerging evidence of expression in non -neuronal cells and it is probable that novel roles outside the nervous system, in relation or not with their ability to
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sense extracellular pH, will be assigned to these channels. For instance, the function of mammalian ASIC4, which is not acti-vated by protons, remains poorly characterized. The multigenic nature of the ASIC family also makes the analysis of multiple ASIC-knockout mice probably necessary to clarify and expand their repertoire of functions in physiological and pathophysi-ological situations both inside and outside the nervous system. Species-specific differences in expression also need to be taken in consideration when evaluating these functions.
Financial & competing interests disclosureWe thank the Association Française contre les Myopathies (AFM), the Agence Nationale de la Recherche (ANR), the Association pour la Recherche sur le Cancer (ARC), the Institut National du Cancer (INCa), and the Institut UPSA de la Douleur (IUD) for financial support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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Key issues
• Acid-sensing ion channels (ASICs) form a family of voltage-independent, excitatory cation channels activated by extracellular protons. They predominantly conduct Na+ and show a very strong dependence on pH.
• ASICs are broadly expressed in the nervous system. Almost all isoforms are present in sensory neurons, while only ASIC1a and ASIC2 have been detected in central neurons in rodents.
• ASICs are nonselectively blocked by amiloride, more selectively blocked by the amidine A-317567, and specifically blocked by two peptide toxins, the spider toxin PcTx1, which inhibits ASIC1a channels, and the sea anemone toxin APETx2, which inhibits ASIC3-containing channels.
• Genetic and pharmacologic data in mice and rats demonstrate a central role for the isoform ASIC1a in the CNS including synaptic plasticity, learning and memory in the hippocampus, and fear, chemosensing and depression in the amygdala.
• ASIC1a has been involved in neuronal degeneration associated with brain acidosis in stroke and neurodegenerative diseases in mice.
• ASIC1a contributes to seizure termination by CO2 and low pH
in mice.
• ASIC1a participates in the central modulation of pain through an interaction with the endogenous opioid system (inhibition of ASIC1a activates the endogenous enkephalin pathway).
• Genetic and pharmacologic data in rodents demonstrate a crucial role for the isoform ASIC3 in the peripheral nervous system in somatic and visceral pain, including inflammation-related pain, chronic muscular pain, angina, arthritis and gastritis, as well as inflammatory and noninflammatory bowel disorders.
• ASICs have also been involved in rodents in mechanosensation, retinal function, baroreceptor reflex, carotid body chemotransduction, hearing and sour-taste perception, and have been detected in many other tissues (e.g., testis, vascular smooth muscle cells, pituitary gland, epithelial cells, immune cells and bone).
• Inhibitors of ASICs may, therefore, constitute new therapeutic tools in the management of psychiatric disorders, neurodegenerative diseases (inhibitors of ASIC1a), and pain (inhibitors of ASIC1a and/or ASIC3), while activators of ASIC1a could be beneficial for seizure treatment.
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