Review

TRENDS in Neurosciences

Vol.29 No.10

Acid-sensing ion channels: advances,

questions and therapeutic
opportunities
John A. Wemmie1,2, Margaret P. Price3 and Michael J. Welsh3,4,5
1

Department of Psychiatry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Department of Veterans Affairs Medical Center, Iowa City, IA 52242, USA
3
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
4
Department of Physiology and Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City,
IA 52242, USA
5
Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
2

Extracellular acid can have important effects on neuron

function. In central and peripheral neurons, acid-sensing
ion channels (ASICs) have emerged as key receptors for
extracellular protons, and recent studies suggest diverse
roles for these channels in the pathophysiology of pain,
ischemic stroke and psychiatric disease. ASICs have also
been implicated in mechanosensation in the peripheral
nervous system and in neurotransmission in the central
nervous system. Here, we briefly review advances in our
understanding of ASICs, their potential contributions to
disease, and the possibility for their therapeutic
modification.
Introduction
Acid-sensing ion channels (ASICs) represent an H+-gated
subgroup of the degenerin/epithelial Na+ channel (DEG/
ENaC) family of cation channels (Box 1, Figure 1). In this
article we review emerging roles of ASICs, both physiological and pathological, and discuss their therapeutic potential. The sections are organized as questions to emphasize
what we consider to be important areas for future research.
Where are ASICs located?
Understanding the physiological function of ASICs
requires knowledge of their cellular and subcellular location. In the peripheral nervous system (PNS), several
recent studies show that some ASIC subunits are well
positioned to function as sensory receptors, for example
in specialized nerve endings (Box 2, Figure 2a). Reports on
their location in the brain have differed: some evidence
places ASIC1a at synapses [1,2], most likely in the postsynaptic membrane, whereas other data suggest it might
be located throughout the neuron [3,4] (Box 2, Figure 2b).
These observations raise the possibility that ASICs function at multiple subcellular locations. More work is needed
to learn how the distribution and proportions of all subunits vary in different cells and under different physiological conditions.
Corresponding authors: Wemmie, J.A. (john-wemmie@uiowa.edu);
Welsh, M.J. (michael-welsh@uiowa.edu).
Available online 7 August 2006.
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What activates ASICs in vivo?

Extracellular protons are crucial for ASIC activation.
ASICs are gated by extracellular protons and are largely
responsible for the acid-evoked currents first observed
many years ago in neurons cultured from the PNS and
CNS [57]. In medium-diameter dorsal root ganglion
(DRG) neurons, acid-activated currents closely match
those from heterologous cells expressing ASIC1, ASIC2
and ASIC3 subunits [8]. Moreover, in such DRG neurons
from mice missing individual ASIC subunits, the H+-gated
currents matched those obtained in Chinese hamster ovary
(CHO) cells expressing the subunits that remained [810]
(Figure 1b). The situation is similar in CNS neurons, where
H+-gated currents probably represent a mix of complexes
containing ASIC1a, ASIC2a and ASIC2b [7,11,12]. However, in contrast to the PNS, in CNS neurons ASIC1a has a
particularly important role. Disrupting the gene encoding
ASIC1a eliminated pH-5-evoked current in cultured hippocampal, amygdala and cortical neurons [2,11]
(Figure 1b). And an antagonist specific for ASIC1a homomultimers (PcTX-1, from tarantula venom) inhibited a
significant proportion of the acid-evoked current in cultured hippocampal neurons [13,14].
Thus, in vivo ASICs are likely to affect neuron function
in response to extracellular acid. But this proposition
raises two questions. First, how sensitive are these channels to pH reductions? Second, does in vivo pH fall to levels
sufficient for ASIC activation? In cultured neurons, pH
values
7.2 [10,15,16] can activate these currents, suggesting that they can respond to very small pH changes. In the
PNS, extracellular pH is well known to drop below 7 under
various conditions [1722]. In the CNS, electrical stimulation can lower extracellular pH in hippocampal slices and
in vivo [23,24]. Synaptic vesicle pH is 5.25.7 [25], and so
during neurotransmission synaptic cleft pH can fall. In
retinal ganglion synapses, neurotransmission lowers pH
sufficiently to inhibit presynaptic Ca2+ channels, suggesting that pH changes in the synaptic cleft can be significant
[26,27]. In the postsynaptic membrane, ASICs are ideally
positioned to respond to these localized pH reductions
(Figures 2b and 3).

0166-2236/$ see front matter 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2006.06.014

Review

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Box 1. Acid-sensing ion channels

ASICs are members of the DEG/ENaC family, which is characterized
by two transmembrane domains, a large cysteine-rich extracellular
domain, and several small conserved amino acid motifs (Figure 1a;
for recent review see Refs [54,55,83]). At least three genes (Accn2,
Accn1 and Accn3) and their alternatively spliced transcripts (ASIC1a,
ASIC1b, ASIC2a, ASIC2b and ASIC3) produce subunits that are
activated by acid or modulate other ASIC subunits [84] (Figure 1b).
They are preferentially permeable to Na+, but to a lesser extent can
also conduct other cations (e.g. Ca2+, K+, Li+ and H+). ASICs are
expressed in neurons and assemble into homomultimeric and
heteromultimeric complexes. It is not known precisely how many
subunits are required to form a channel, but stoichiometric studies
with other DEG/ENaC channels suggest four to nine [85,86]. In
heterologous cells, ASIC homomultimeric channels vary in terms of
activation and desensitization kinetics (Figure 1b) and pH sensitivity.
For example, in one study, the pH values required for half-maximal
activation (pH0.5) of mouse ASIC subunits were 6.8 (ASIC1a), 6.2
(ASIC1b), 4.9 (ASIC2a) and 6.6 (ASIC3) [8]. There might also be
differences in pH sensitivity between species, for example ASIC3
might be the most sensitive subunit in rat (pH0.5 = 6.7) [10].
Coexpressing various subunits produces heteromultimers, with
H+-gated currents revealing characteristics that in some cases reflect
average properties of contributing subunits and in other cases
properties that lie outside the range of the individual subunits (e.g.
rate of desensitization) [8,9,50,87]. Subunit composition also alters
ion selectivity; for example ASIC1a homomultimeric complexes are
permeable to Ca2+, whereas ASIC2-containing heteromultimeric
complexes are not [65]. Two additional genes, encoding ASIC4 [88]
and BLINaC [89], are expressed in neurons but have not yet been
shown to produce or modulate H+-evoked currents. In addition,
ENaC subunits have been detected in some neurons, where they
might contribute to sensory function [90].

Despite these compelling arguments, attempts so far

have failed to detect ASIC activation during neurotransmission in hippocampal slices or in cultured neurons [2,3].
Our interpretation of these studies is either that ASIC1a is
not activated during neurotransmission or that appropriate tests of ASIC activation at the synapse have not been
identified. More information is needed to understand
clearly the role of ASIC1a in synaptic physiology.
What else does the large extracellular ASIC domain do?
Are there other ligands?
The large size of the ASIC extracellular domain (318 of
the 528 residues in ASIC1a), with its 14 conserved cysteine
residues, suggests a rigid structure and evokes the image
of an antenna protruding above the channel pore
(Figure 1a). It would be surprising if such a complex
structure exists solely to sense protons, so we speculate
that other ligands might exist. Perhaps unrecognized
ligands are released during neurotransmission. Fuelling
this speculation, FMRFamide, a neurotransmitter peptide
from molluscs, modulates activation of ASICs by protons
[28]. Many other factors also interact with the extracellular
domain to modulate H+-dependent channel activity; these
include Zn2+ [29], Ca2+ [16], lactate [30], proteases [31],
arachidonic acid [32], lead [33] and redox reagents [34]
(Figure 3). Conversely, why do protons fail to activate some
ASICs (ASIC2b and ASIC4)? Perhaps these subunits contribute only to heteromultimeric channels that also contain
H+-gated subunits, or maybe they have specific ligands of
their own. Certainly there are other DEG/ENaC subunits
for which we do not yet know the ligands for example, the
related subunits from fish, some of which are insensitive to
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acid [35,36], and the Drosophila [37] and Caenorhabditis

elegans DEG/ENaC subunits.
We speculate that ASIC extracellular domains will turn
out to possess additional functions. For example, they
might bind components of the extracellular matrix.
Genetic data from C. elegans suggest that interactions
with the extracellular matrix are functionally important
for mechanosensitive DEG/ENaC channels (e.g. Mec-4 and
Mec-10) [38]. Because ASICs are implicated in mechanosensation, binding to the extracellular matrix could support a tethered mechanism by which movement regulates
channel opening. In addition, if the extracellular domain
protrudes a substantial distance from the cell surface, it
might contact proteins on other cells, an interaction that
could influence function.
What is the physiological significance of ASICs in the
PNS?
Their location and properties make ASIC subunits attractive candidates to serve as H+-gated nociceptors. It is
known that peripheral pH falls to <7 with inflammation,
infection, ischemia, hematomas and exercise [1722].
Moreover, such acidosis is well recognized to activate
nociceptors and produce pain in humans that can be attenuated by the DEG/ENaC inhibitor amiloride [3941].
Variations in subunit composition would also enable
ASICs to detect a broad pH range and thereby sense
variations in the intensity of noxious stimuli [8]. In addition, inflammatory mediators such as nerve growth factor
(NGF), 5-hydroxytryptamine (5-HT or serotonin), interleukin-1, bradykinin and brain-derived neurotrophic factor
(BDNF) can stimulate ASIC transcription, which perhaps
contributes to the pain-enhancing effects of these mediators [4244].
Although it seemed that studying gene-targeted mice
would clarify the role of ASICs in acid-induced nociception,
reports to date give a mixed picture. Some data suggest
that loss of ASIC3 reduces the painful response to an acidic
stimulus. For example, in the isolated skinnerve preparation a pH 5 stimulus generated a reduced response in Cmechanoheat fibers of ASIC3 null animals [45]. In addition, repeated injection of acidic saline into muscle produced long-lasting mechanical hyperalgesia in wild-type
but not ASIC3/ mice [46]. Amiloride pretreatment also
attenuated the response in wild-type animals. Based on
these data, we expected that disrupting ASIC3 would blunt
the behavioral response to acid injection into the paw.
However, ASIC3 null mice behaved like wild-type mice
[45]. Even more puzzling, in a different ASIC3 knockout
mouse, intraperitoneal acid injection elicited a greater
behavioral response than in wild-type mice [47]; painful
mechanical and thermal stimuli also generated an
enhanced behavioral response. Although ASIC1a is as
sensitive to pH as ASIC3 and is expressed in DRG neurons,
ASIC1a null mice were no different from wild-type animals
either in the skinnerve preparation or in tests of mechanical hyperalgesia [46,48]. In transgenic mice overexpressing a dominant-negative ASIC3, the response to thermal
stimuli was normal, but the animals showed an increased
response to intraperitoneal acid injection and mechanical
hypersensitivity after inflammatory stimuli [49].

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Figure 1. ASIC subunits and activation by extracellular acid. (a) Topology of ASIC1a protein. Adapted, with permission, from Ref. [54]. (b) Acid-evoked currents in
heterologous cells (Cos-7 cells) expressing the indicated ASIC subunits. (c) H+-evoked currents in cultured wild-type dorsal root ganglion (WT DRG) neurons (i) resemble
currents from heterologous cells expressing a combination of ASIC subunits (ii). Currents from DRG neurons cultured from ASIC3/ mice (iii) resemble currents produced
by coexpressing ASIC1a and ASIC2a in Cos-7 cells (iv). (d) Loss of ASIC1a eliminates pH-5-evoked current in neurons cultured from the CNS (hippocampus), whereas loss of
ASIC2 has more subtle effects. Panels (bd) adapted, with permission, from Ref. [2], Ref. [8] (2002) National Academy of Sciences, and Ref. [11].

At present it seems safe to say that ASICs can modulate

the response to some painful stimuli. But it remains difficult to make simple generalizations about the contribution
specific ASICs make to acid-induced nociception or other
painful stimuli, and we are left with several questions.
First, do ASICs serve as receptors for acid that elicits
peripheral pain? This seems likely in some cases, but
the aforementioned data leave much uncertainty. Contributions from multiple different ASIC subunits, the assays
utilized, ASIC-associated proteins, compensatory changes
and mouse strain differences could all cloud
interpretations.
Second, can ASICs produce a response to sustained
acidosis? ASIC currents are largely transient, whereas
nociceptive acidosis can persist for hours to days. Because
they rapidly desensitize, some have considered ASICs best
suited to respond to rapid, transient pH fluctuations.
However, ASICs can manifest a persistent current
[8,50], particularly when activated in the presence of neuropeptides such as NPFF or FMRFamide [28]. In addition,
an overlap between activation and desensitization kinetics
suggests that even mild pH changes lead to a small but
persistent ASIC-mediated depolarization [4,15,51]. Thus,
it seems likely that chronic acidic conditions foster ASIC
activity.
Third, why are acid-activated currents not detected in
peripheral endings of mechanoreceptive nerve fibers in
skin? In culture, large-diameter mechanosensory DRG
neurons express ASICs and manifest H+-gated currents.
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Moreover, in the skin, peripheral nerve endings contain

ASICs, which are required for normal mechanoreceptor
function [45,52]. Yet paradoxically, acid does not elicit
activity from these endings in a skinnerve preparation
[53]. Possibly ASICs at these sites are H+ gated under some
conditions, but the resulting current fails to depolarize
membranes sufficiently for action potentials to occur.
Alternatively, in mechanosensory nerve terminals, extracellular and intracellular proteins perhaps tether ASICs to
confer touch sensitivity and in so doing mask pH-sensitive
sites or somehow preclude activation by H+. It is also
possible that ASIC activation might require more than
one stimulus at these sites. These considerations suggest
that ASICs might be strongly influenced by the local
environment and perhaps by their interacting partners.
What is the role of ASICs in mechanosensation?
The similarity between ASICs and the mechanoreceptors
(Mec-4 and Mec-10) from C. elegans suggested that ASICs
might contribute to mechanosensation (for more detailed
reviews, see Refs [54,55]). Initially, we anticipated that
disrupting the ASICs might cause a striking loss of function akin to disrupting DEG/ENaC subunits in C. elegans
[56]. But the ASIC effects were more subtle and in some
cases perplexing [54]. In one study, the sensitivity of lowthreshold, rapidly adapting mechanoreceptors was
reduced in ASIC2 null animals [52], but another study
using a different ASIC2 null reported no effect [57].
ASIC1a null mice showed normal responsiveness in a

Review

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Box 2. Localization of ASIC subunits

In the PNS, ASIC subunits localize to neurons innervating skin
[45,52,91], heart [15], gut [92,93] and muscle [94]. They have also
been detected in the eye [95,96], ear [97,98], taste buds [99] and
bone [73]. The localization has been characterized most thoroughly
in cutaneous neurons. ASIC subunits have been detected in large,
medium and small DRG neurons, although the subunit composition
varies among DRG neurons of different sizes, producing heterogeneity in H+-evoked currents [100102]. Immunocytochemical
studies find both ASIC2 and ASIC3 in specialized cutaneous nerve
endings, such as Meissners corpuscles (Figure 2a), palisades of
lanceolate fibers that surround hair shafts, Pilo-Ruffini nerve endings and Merkel cells, and in small free nerve endings in the
epidermis [45,52].
In contrast to the PNS, transcript analysis in the brain shows that
ASIC1a, ASIC2a and ASIC2b have relatively widespread distribution
[61,62,103,104]. ASIC3 is abundantly expressed in DRG and spinal
cord, but little or no ASIC3 is expressed in rodent brain [105,106].
ASIC1a immunostaining and western blotting suggest that ASIC1a
subunits might be particularly enriched in some brain regions,
including the glomerulus of the olfactory bulb, whisker barrel
cortex, cingulate cortex, striatum, nucleus accumbens, amygdala
and cerebellar cortex [1]. At the subcellular level, ASIC1a is present
in the cell body and preferentially localized to dendrites and
dendritic spines (Figure 2b), where it colocalized with the postsynaptic density protein PSD-95. These studies benefited from use
of ASIC1a null mice as a negative control. Consistent with this work,
ASIC1a was also enriched in synaptosome-containing fractions
from brain [13,63]. However, another immunohistochemical study
suggested that ASIC1a might be present in membranes throughout
neurons, including axons, with no preferential distribution to
synapses [3]. Although differences in antibody specificity might
explain the incongruity, additional studies are needed to clarify the
precise location of ASIC1a. Compared with ASIC1a, less is known
about the distribution of ASIC2, although it has been suggested that
ASIC2a is present in the postsynaptic membrane of granule cells
and Purkinje cells of the cerebellum [107]. ASIC1, ASIC2, ASIC3 and
ASIC4 have also been detected in the retina, where pH has an
important role in synaptic physiology [27,95,96,108,109].

skinnerve preparation [48], whereas ASIC3/ mice

manifested increased sensitivity of rapidly adapting
mechanoreceptors [45]. Moreover, mice transgenic for a
dominant-negative ASIC3 that inhibited much of the acidevoked current showed increased behavioral responses to
mechanical stimuli [49]. In splanchnic colonic afferents
and vagal gastroesophageal afferents, disrupting ASIC1a

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increased the mechanical sensitivity, disrupting ASIC2

had varied effects depending on the location, and disrupting ASIC3 reduced the mechanosensitivity of all afferent
classes except gastroesophageal mucosal receptors [48,58].
Interestingly, mechanical stimulation of cultured DRG
neurons revealed no difference between ASIC2 and/or
ASIC3 null mutants and wild-type controls [59].
How can these seemingly disparate observations be
reconciled into a unifying hypothesis? The data indicate
that ASICs influence mechanosensation. But their role
seems complex. At present there is no direct evidence
establishing them as mechanosensors. Perhaps redundancy of DEG/ENaC channels and/or the presence of other
sensory receptors including transient receptor potential
(TRP) channels preclude simple all-or-nothing effects. Perhaps ASICs somehow modulate transduction by other
molecules. Perhaps various ASICs can have activating
or inhibiting roles depending on their partners and locations. Perhaps compensatory effects occur in knockout and
transgenic animals. Or perhaps ASIC activation by
mechanical stimuli requires a specific intracellular and/
or extracellular milieu. To understand how ASICs influence mechanical sensation, we need to know whether they
can be gated by mechanical stimuli and how they influence
other sensors.
What is the physiological significance of ASICs in the
CNS?
Based on studies of mice with targeted disruption of the
gene encoding ASIC1a and transgenic mice overexpressing
ASIC1a, we know more about ASIC1a than the other ASIC
subunits. Loss of ASIC1a disrupted hippocampal-dependent LTP and spatial memory in the Morris water maze [2].
These results indicate that ASIC1a modulates synaptic
plasticity and contributes to learning and memory. However, the spatial learning effects were modest [1], perhaps
because hippocampal pyramidal cells express relatively
low levels of ASIC1a [1].
By contrast, the molecular layer of the cerebellar cortex
expresses abundant ASIC1a and acidosis elicits large H+gated currents in Purkinje cells [1,32]. Accordingly, loss of

Figure 2. Subcellular distribution of ASICs. (a) ASIC3 immunostaining in a Meissners corpuscle. S100 immunostaining was used to identify the corpuscle positively. Scale
bar, 100 mm. Adapted, with permission, from Ref. [45]. (b) ASIC1a immunostaining in dendritic spines. In a cultured hippocampal neuron transfected with cDNA constructs
expressing green fluorescent protein (GFP, green) and ASIC1a (red), ASIC1a appears in the spinous processes extending off the dendritic tree, suggesting it is closely
associated with the postsynaptic membrane. Scale bar, 10 mm.
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Figure 3. Model for ASIC1a activation at the synapse. In the postsynaptic membrane, ASICs might be well positioned to respond to protons released from presynaptic neurotransmitter (NT)-containing vesicles and also from other sources.
Various extracellular modulators and intracellular ASIC-interacting proteins
(boxes) might influence the response, which would be expected to depolarize
the membrane potential and raise intracellular Ca2+ concentration, perhaps
influencing other receptors and signaling proteins. This model makes two predictions that should be tested experimentally. First, it predicts that pH will fall in the
synaptic cleft during neurotransmission. This technically challenging measurement might now be feasible with new pH-sensitive fluorophores. Second, this
model predicts that ASIC1a currents will be activated during neurotransmission.
So far, studies in brain slices [2] and cultured neurons [3] have not detected them.
There are many potential explanations for these negative results, but they hint that
the story is more complex; perhaps ASICs require additional conditions for
activation or interactions with other proteins through the extracellular domain. For
abbreviations, see Table 1 and the main text.

ASIC1a considerably impaired cerebellum-dependent

learning assessed by eye-blink conditioning [2]. ASIC1a
expression and acid-evoked currents are also substantial
in the amygdala complex, which is important in fearrelated behavior [1,6062]. Consistent with this, mice with
a disruption of the gene encoding ASIC1a showed a
reduced fear response (e.g. freezing behavior) to both cued
and context-specific Pavlovian fear conditioning
(Figure 4a) [1]. Conversely, overexpressing ASIC1a in
the amygdala and elsewhere in the brain increased H+evoked currents and enhanced context fear conditioning,
providing an animal model of acquired anxiety [63].
Yet the underlying mechanisms linking ASIC1a function to these behavioral effects remain poorly understood.
Because ASIC1a conducts Ca2+ [62,64,65] and interacts
with Ca2+/calmodulin-dependent kinase (CaMKII) [66], we
wonder whether a resulting increase in Ca2+ is responsible.
Other questions also arise. Does ASIC1a augment neurotransmission? Do ASICs stimulate or inhibit action potentials [4]? Are ASIC1a homomultimers or heteromultimers
responsible for these effects? Do ASIC2 and other DEG/
ENaC subunits modify the function of ASIC1a in brain, or
do they have independent functions?
What is the physiological significance of interactions
with other proteins?
Most membrane proteins reside in macromolecular complexes, and ASICs are no exception: several ASIC-interacting proteins have already been identified (Table 1) and
more are likely to exist. Possibly the interacting partners
dictate the diverse physiological roles of these channels.

Figure 4. Loss of ASICs disrupts conditioned fear and pain. (a) On day 1, animals received aversive footshocks, which were paired with the training environment (context) or
a tone. On day 2, the conditioned freezing responses to the context and tone were measured. Disruption of the gene encoding ASIC1a reduced the freezing response on day
2 to both context and tone. Adapted, with permission, from Ref. [1] (2003) Society for Neuroscience. (b) Paw withdrawal before and after intramuscular injection of acid
(pH 4.0). Disruption of the gene encoding ASIC3 reduced post-injection hyperalgesia. Adapted, with permission, from Ref. [45]. Asterisks indicate P < 0.05.
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Table 1. Interactions of ASIC subunits with scaffolding proteins, and effects on ASIC propertiesa
Protein
PICK1
CaMKII
PSD-95
Lin7B
MAGI-1b
PIST
CIPP
Stomatin
Stomatin
Stomatin
NHERF
Annexin II/p11 1

ASIC subunits
1, 2
1
3
3
3
3
3
1
2
3
3
1

Site of interaction b
C terminus
NR
C terminus
C terminus
C terminus
C terminus
C terminus
NR
NR
NR
C terminus
N terminus

Current amplitude c
$
"
#
"
"
"
"
$
$
#
"
"

Gating properties
NR
NR
$
$
NR
NR
# pH sensitivity
$
" desensitization
$
$
$

Surface expression
NR
NR
#
"
NR
NR
NR
NR
NR
$
"
"

Refs
[6769]
[66]
[106]
[106]
[106]
[106]
[110]
[111]
[111]
[111]
[112]
[70]

Symbols: ", increases; #, decrease; $, no change. Abbreviations: CaMKII, Ca2+/calmodulin-dependent kinase II; CIPP, channel-interacting PDZ domain protein; Lin7B,
abnormal cell lineage 7B; MAGI-1b, membrane-associated guanylate kinase with inverted orientation-1b; NHERF, Na+/H+ exchanger regulatory factor 1; NR, not reported;
PICK1, protein interacting with C-kinase 1; PIST, PDZ-domain protein interacting specifically with TC10; PSD-95, postsynaptic density protein 95.
b
Where investigated, binding to the C terminus of ASIC subunits has been through the PDZ domain of the indicated protein.
c
Peak whole-cell current amplitude in response to acid application.

We imagine a dynamic interplay with multiple proteins

shuttling ASICs to specialized sensory receptors and
synapses, or stabilizing them once they are there. They
might regulate ligand binding, channel opening and closing, and second-messenger signaling. These interactions
could also regulate protein turnover, or the assembly of
channel subunits into homomeric and heteromeric complexes. Interactions with other channels and transporters
are also a possibility.
Although current knowledge is inadequate, it does support several conclusions. First, not all ASICs interact with
the same partners. For example, protein interacting with C
kinase (PICK)1 interacts directly with ASIC1 and ASIC2,
but not ASIC3 [6769]. Second, some interactions occur via
the C-terminal PDZ domains (Table 1), at least one (with
annexin) occurs via the N terminus [70], and for others the
interacting sites have not yet been identified. Third, at
least two interactions (with PICK1 and CaMKII) facilitate
channel phosphorylation [69,71]. Fourth, some interactions affect channel gating properties whereas others
might increase or decrease channel density on the cell
surface (Table 1). Each of these interactions might have
important consequences, but much remains to be learned.
For example, which interactions occur in vivo, and what
are their physiological effects? A detailed knowledge of
these interactions is crucial if we are to understand how
ASICs function in complex systems.
What are the roles of ASICs in pathophysiology,
and are there therapeutic opportunities?
From what we have learned so far, there is an emerging
appreciation for how ASICs might contribute to disease
and to novel therapies. Here we consider a few examples.
Pain
There is an enormous need for better medications to treat
both acute and chronic pain, so the possibility of targeting
ASICs has substantial appeal. The idea that inhibiting
ASICs might relieve pain in humans received a significant
boost when the DEG/ENaC antagonist amiloride attenuated the pain of intradermal acid infusion [40,41]. Although
amiloride can have other effects, it failed to inhibit capsaicin-induced pain, and capsaizapine, an inhibitor of vanilloid
receptor 1 (VR1), did not relieve acid-evoked pain. These
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results suggested that ASICs, rather than VR1, mediated

pain induced by acid injection. In addition, an agent (A317567) that inhibits ASIC1, ASIC2 and ASIC3 subunits
also attenuated post-operative skin-incision pain in rats
[72]. Furthermore, non-steroidal anti-inflammatory drugs
(NSAIDs) reduced ASIC expression and inhibited ASIC
currents in rat sensory neurons [42,43].
One of the first suggestions that ASICs might be
involved in visceral pain came with the observation that
cardiac afferents express ASIC3 currents, which might
mediate the pain of ischemic angina [10,15]. In addition,
recent data show that ASICs affect the response to gut
distension [48,58]. Because mechanical stimulation can
influence autonomic control of digestion and can evoke
feelings of bloating, cramping and pain, ASICs might be
good targets for combating visceral discomfort. ASICs
might also be involved in pain at several locations. Their
expression in nerves innervating joints and bone positions
them to sense the acidosis that arises in chronic inflammatory arthritides and cancer metastases [73,74]. ASICs
in muscle afferents might detect the lactic acidosis of
severe exercise. Sickle cell disease can cause ischemia with
crippling pain; perhaps ASICs detect the resulting pH
reduction [75].
We wonder whether targeting either specific ASIC subunits or all ASICs might yield novel treatments for common pain syndromes. Attempts to develop toxins [13,76]
and small molecule ASIC inhibitors [72] could yield new
tools to investigate these possibilities. However, as we
have already described, although several studies suggest
ASIC inhibition might reduce pain, some mouse data
suggest disrupting ASICs might increase sensitivity to
painful stimuli. The explanations for such differences
remain unclear, but might include variability in genetic
background or species, differences in testing paradigms,
and environmental variability. Or it might be that ASICs
affect pain in ways more complex than originally appreciated. We clearly need to know more about the physiological role of ASICs in pain before we can take full
advantage of their therapeutic potential.
Ischemic stroke
Recent studies have generated significant interest in
ASICs as possible therapeutic targets for stroke. Severe

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cerebral ischemia can cause pH to drop to 6.3 and below

[77,78]. Because Ca2+ overload causes toxicity in the
ischemic brain, and because ASIC1a homomultimers conduct Ca2+ [65], ASIC1a activation could contribute to the
cell damage and death of cerebral ischemia. Enhancement
of ASIC1a function by activation of NMDA receptors, lack
of oxygen or glucose, or accumulation of lactate or arachidonic acid might further enhance ASIC1a-mediated neurotoxicity [66]. The hypothesis that ASIC1a contributes to
ischemic toxicity was recently tested in cells heterologously
expressing ASIC1a and in hippocampal neurons [6466].
Neurons lacking ASIC1a and cells treated with amiloride
or PcTX-1 resisted acidosis-induced injury. Moreover,
PcTX-1 diminished the effects of NMDA-induced cell death
[64,66]. Another key finding came from a mouse model in
which middle cerebral artery occlusion causes an ischemic
stroke [64]. Remarkably, disrupting ASIC1a reduced
infarct volume by 60%. Because pH remains low for hours
after a stroke, ASIC1a inhibitors might be beneficial for
some time after an ischemic event [79]. These results
recommend ASIC1a inhibitors as a potential new treatment for stroke. Likewise, we wonder whether increasing
ASIC2a expression might be neuroprotective by forming
heteromultimers of ASIC1a and ASIC2a that do not conduct Ca2+. Consistent with this possibility, ASIC2a expression is increased following global ischemia, perhaps
serving a neuroprotective function [80].
Psychiatric disease
We currently know of no psychiatric disease caused by a
loss or gain of ASIC function. But several factors lead us to
predict that a link to psychiatric disease will be discovered.
First, ASIC1a is located at synapses and modulation of
synaptic physiology is likely to have behavioral consequences. Second, expression of ASIC1a, ASIC2a and
ASIC2b in the brain is robust. Third, the loss of ASIC1a
in mice had several behavioral effects, suggesting that
similar consequences might carry over to humans.
What psychiatric manifestations could be associated
with ASIC1a mutations? ASIC1a is particularly abundant
in the amygdala and other brain regions implicated in
anxiety, and the loss of ASIC1a has pronounced effects
on fear-related behavior [1]. Moreover, because the anatomy and physiology of fear conditioning are well conserved
between species and ASIC1a is expressed in the human
amygdala [1,63], we anticipate that disrupted ASIC1a
function would reduce fear in humans. Because reduced
fear has been suggested to increase risk-taking behavior
[81]; this personality trait might be associated with a loss of
ASIC1a function. Conversely, analysis of mice overexpressing ASIC1a suggests that humans with gain-of-function
mutations might be prone to fearful behavior. They might
also be supersensitive to acidosis. Interestingly many
patients with panic disorder have panic attacks when
breathing CO2 [82]. Because CO2 lowers brain pH, we
wonder whether ASIC1a might have a role in CO2-evoked
panic.
Irrespective of whether ASIC genes contribute to disease pathogenesis, manipulating ASIC1a function pharmacologically might provide a novel strategy for reducing
fear and anxiety in patients. The relative abundance of
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ASIC1a in the fear circuit and its robust effect on

fear-related behavior suggest that ASIC1a antagonists
might offer advantages over current treatments, which
target the GABA and 5-HT systems. In mice, the effect
of ASIC1a on hippocampus-dependent memory was relatively subtle; thus, in humans the effect of ASIC1a antagonists on declarative memory might be small [2].
Furthermore, several other non-fear-related behaviors
were intact in the ASIC1a null mice [1,2], suggesting
ASIC1a antagonists might reduce anxiety with relative
specificity.
In conclusion, our knowledge of ASICs is rapidly
increasing. We have learned much about their localization,
and their biochemical, physiological and pathophysiological effects. This knowledge raises additional mechanistic
questions. However, it also increases our appreciation that
ASICs might be excellent targets for treating neurological
disease.
Acknowledgements
J.A.W. was supported by the Department of Veterans Affairs Advanced
Research Career Development Award, NARSAD Young Investigatory
Award, and ADAA Young Investigator Award. M.J.W. is an Investigator
of the HHMI.

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