Alzheimer’s disease prevalence has reached epidemic proportion with very few treatment options, which are associated with a multitude of side effects. A potential avenue of research for new therapies are protons, and their associated receptor: acid-sensing ion channels (ASIC). Protons are often overlooked neurotransmitters, and proton-gated currents have been identified in the brain. Furthermore, ASICs have been determined to be crucial for proper brain function. While there is more work to be done, this review is intended to highlight protons as neurotransmitters and their role along with the role of ASICs within physiological functioning of the brain. We will also cover the pathophysiological associations between ASICs and modulators of ASICs. Finally, this review will sum up how the studies of protons, ASICs and their modulators may generate new therapeutic molecules for Alzheimer’s disease and other neurodegenerative diseases.
JackCRJr, AlbertMS, KnopmanDS, McKhannGM, SperlingRA, CarrilloMC, ThiesB, PhelpsCH (2011) Introduction to the recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement7, 257–262.
2.
Alzheimer’s Association (2015) 2015 Alzheimer’s disease facts and figures. Alzheimers Dement11, 332–384.
3.
Alzheimer’s Association (2016) 2016 Alzheimer’s disease facts and figures. Alzheimers Dement12, 459–509.
4.
HebertLE, WeuveJ, ScherrPA, EvansDA (2013) Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology80, 1778–1783.
5.
BrookmeyerR, JohnsonE, Ziegler-GrahamK, ArrighiHM (2007) Forecasting the global burden of Alzheimer’s disease. Alzheimers Dement3, 186–191.
6.
Keogh-BrownMR, JensenHT, ArrighiHM, SmithRD (2016) The impact of Alzheimer’s disease on the chinese economy. E Bio Medicine4, 184–190.
7.
WuYT, FratiglioniL, MatthewsFE, LoboA, BretelerMM, SkoogI, BrayneC (2016) Dementia in western Europe: Epidemiological evidence and implications for policy making. Lancet Neurol15, 116–124.
8.
BanerjeeTK, DuttaS, DasS, GhosalM, RayBK, BiswasA, HazraA, ChaudhuriA, PaulN, DasSK (2016) Epidemiology of dementia and its burden in the city of Kolkata, India. Int J Geriatr Psychiatry, doi: 10.1002/gps.4499
9.
HickmanRA, FaustinA, WisniewskiT (2016) Alzheimer disease and its growing epidemic: Risk factors, biomarkers, and the urgent need for therapeutics. Neurol Clin34, 941–953.
DuJ, ReznikovLR, PriceMP, ZhaXM, LuY, MoningerTO, WemmieJA, WelshMJ (2014) Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala. Proc Natl Acad Sci U S A111, 8961–8966.
14.
CheslerM (2003) Regulation and modulation of pH in the brain. Physiol Rev83, 1183–1221.
DeVriesSH (2001) Exocytosed protons feedback to suppress the Ca2+ current in mammalian cone photoreceptors. Neuron32, 1107–1117.
17.
De GrotthussCJ (1806) Sur la decomposition de l’eau et des corps qu’elle tient en dissolution a l’aide de l’electricite galvanique. Ann Chim58, 54–73.
18.
de GrotthussCJ (2006) Memoir on the decomposition of water and of the bodies that it holds in solution by means of galvanic electricity. 1805. Biochim Biophys Acta1757, 871–875.
19.
JastiJ, FurukawaH, GonzalesEB, GouauxE (2007) Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature449, 316–323.
20.
KrishtalOA, PidoplichkoVI (1980) A receptor for protons in the nerve cell membrane. Neuroscience5, 2325–2327.
21.
PriceMP, SnyderPM, WelshMJ (1996) Cloning and expression of a novel human brain Na+ channel. J Biol Chem271, 7879–7882.
22.
WaldmannR, ChampignyG, VoilleyN, LauritzenI, LazdunskiM (1996) The mammalian degenerin MDEG, an amiloride-sensitive cation channel activated by mutations causing neurodegeneration in Caenorhabditis elegans. J Biol Chem271, 10433–10436.
23.
QadriYJ, RoojAK, FullerCM (2012) ENaCs and ASICs as therapeutic targets. Am J Physiol Cell Physiol302, C943–C965.
24.
LinguegliaE, de WeilleJR, BassilanaF, HeurteauxC, SakaiH, WaldmannR, LazdunskiM (1997) A modulatory subunit of acid sensing ion channels in brain and dorsal root ganglion cells. J Biol Chem272, 29778–29783.
25.
ChenCC, EnglandS, AkopianAN, WoodJN (1998) A sensory neuron-specific, proton-gated ion channel. Proc Natl Acad Sci U S A95, 10240–10245.
26.
GrunderS, ChenX (2010) Structure, function, and pharmacology of acid-sensing ion channels (ASICs): Focus on ASIC1a. Int J Physiol Pathophysiol Pharmacol2, 73–94.
27.
WiemuthD, SahinH, FalkenburgerBH, LefevreCM, WasmuthHE, GrunderS (2012) BASIC–a bile acid-sensitive ion channel highly expressed in bile ducts. FASEB J26, 4122–4130.
28.
BoikoN, KucherV, WangB, StockandJD (2014) Restrictive expression of acid-sensing ion channel 5 (asic5) in unipolar brush cells of the vestibulocerebellum. PLoS One9, e91326.
29.
BensonCJ, XieJ, WemmieJA, PriceMP, HenssJM, WelshMJ, SnyderPM (2002) Heteromultimers of DEG/ENaC subunits form H+-gated channels in mouse sensory neurons. Proc Natl Acad Sci U S A99, 2338–2343.
30.
SherwoodTW, LeeKG, GormleyMG, AskwithCC (2011) Heteromeric acid-sensing ion channels (ASICs) composed of ASIC2b and ASIC1a display novel channel properties and contribute to acidosis-induced neuronal death. J Neurosci31, 9723–9734.
31.
ZiemannAE, AllenJE, DahdalehNS, DrebotII, CoryellMW, WunschAM, LynchCM, FaraciFM, HowardMA3rd, WelshMJ, WemmieJA (2009) The amygdala is a chemosensor that detects carbon dioxide and acidosis to elicit fear behavior. Cell139, 1012–1021.
32.
GrunderS, GeisslerHS, BasslerEL, RuppersbergJP (2000) A new member of acid-sensing ion channels from pituitary gland. Neuroreport11, 1607–1611.
33.
HesselagerM, TimmermannDB, AhringPK (2004) pH Dependency and desensitization kinetics of heterologously expressed combinations of acid-sensing ion channel subunits. J Biol Chem279, 11006–11015.
34.
YagiJ, WenkHN, NavesLA, McCleskeyEW (2006) Sustained currents through ASIC3 ion channels at the modest pH changes that occur during myocardial ischemia. Circ Res99, 501–509.
35.
SlukaKA, GregoryNS (2015) The dichotomized role for acid sensing ion channels in musculoskeletal pain and inflammation. Neuropharmacology94, 58–63.
36.
SmithES, OmerbasicD, LechnerSG, AnirudhanG, LapatsinaL, LewinGR (2011) The molecular basis of acid insensitivity in the African naked mole-rat. Science334, 1557–1560.
37.
BensonCJ, EckertSP, McCleskeyEW (1999) Acid-evoked currents in cardiac sensory neurons: A possible mediator of myocardial ischemic sensation. Circ Res84, 921–928.
38.
BabiniE, PaukertM, GeislerHS, GrunderS (2002) Alternative splicing and interaction with di- and polyvalent cations control the dynamic range of acid-sensing ion channel 1 (ASIC1). J Biol Chem277, 41597–41603.
39.
SmithRN, GonzalesEB (2014) Protons and Psalmotoxin-1 reveal nonproton ligand stimulatory sites in chicken acid-sensing ion channel: Implication for simultaneous modulation in ASICs. Channels (Austin)8, 49–61.
40.
ChenX, GrunderS (2007) Permeating protons contribute to tachyphylaxis of the acid-sensing ion channel (ASIC) 1a. J Physiol579, 657–670.
41.
JoeresN, AugustinowskiK, NeuhofA, AssmannM, GrunderS (2016) Functional and pharmacological characterization of two different ASIC1a/2a heteromers reveals their sensitivity to the spider toxin PcTx1. Sci Rep6, 27647.
42.
WaldmannR, ChampignyG, BassilanaF, HeurteauxC, LazdunskiM (1997) A proton-gated cation channel involved in acid-sensing. Nature386, 173–177.
43.
YermolaievaO, LeonardAS, SchnizlerMK, AbboudFM, WelshMJ (2004) Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc Natl Acad Sci U S A101, 6752–6757.
GruolDL, BarkerJL, HuangLY, MacDonaldJF, SmithTGJr (1980) Hydrogen ions have multiple effects on the excitability of cultured mammalian neurons. Brain Res183, 247–252.
46.
WemmieJA, ChenJ, AskwithCC, Hruska-HagemanAM, PriceMP, NolanBC, YoderPG, LamaniE, HoshiT, FreemanJHJr, WelshMJ (2002) The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory. Neuron34, 463–477.
47.
ZhaXM, WemmieJA, GreenSH, WelshMJ (2006) Acid-sensing ion channel 1a is a postsynaptic proton receptor that affects the density of dendritic spines. Proc Natl Acad Sci U S A103, 16556–16561.
48.
WemmieJA, AskwithCC, LamaniE, CassellMD, FreemanJHJr, WelshMJ (2003) Acid-sensing ion channel 1 is localized in brain regions with high synaptic density and contributes to fear conditioning. J Neurosci23, 5496–5502.
49.
ZengWZ, XuTL (2012) Proton production, regulation and pathophysiological roles in the mammalian brain. Neurosci Bull28, 1–13.
50.
WemmieJA, TaugherRJ, KrepleCJ (2013) Acid-sensing ion channels in pain and disease. Nat Rev Neurosci14, 461–471.
51.
ChuXP, XiongZG (2012) Physiological and pathological functions of acid-sensing ion channels in the central nervous system. Curr Drug Targets13, 263–271.
52.
XiongZG, PignataroG, LiM, ChangSY, SimonRP (2008) Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr Opin Pharmacol8, 25–32.
53.
SunX, HeG, QingH, ZhouW, DobieF, CaiF, StaufenbielM, HuangLE, SongW (2006) Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci U S A103, 18727–18732.
54.
YingjunG, XunQ (2013) Acid-sensing ion channels under hypoxia. Channels (Austin)7, 231–237.
55.
ArunT, TomassiniV, SbardellaE, de RuiterMB, MatthewsL, LeiteMI, Gelineau-MorelR, CaveyA, VergoS, CranerM, FuggerL, RoviraA, JenkinsonM, PalaceJ (2013) Targeting ASIC1 in primary progressive multiple sclerosis: Evidence of neuroprotection with amiloride. Brain136, 106–115.
56.
ChuXP, PapasianCJ, WangJQ, XiongZG (2011) Modulation of acid-sensing ion channels: Molecular mechanisms and therapeutic potential. Int J Physiol Pathophysiol Pharmacol3, 288–309.
57.
KapogiannisD, BoxerA, SchwartzJB, AbnerEL, BiragynA, MasharaniU, FrassettoL, PetersenRC, MillerBL, GoetzlEJ (2015) Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer’s disease. FASEB J29, 589–596.
58.
ImmkeDC, McCleskeyEW (2001) Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nat Neurosci4, 869–870.
59.
ChangY, HsiehCY, PengZA, YenTL, HsiaoG, ChouDS, ChenCM, SheuJR (2009) Neuroprotective mechanisms of puerarin in middle cerebral artery occlusion-induced brain infarction in rats. J Biomed Sci16, 9.
60.
YifengM, BinW, WeiqiaoZ, YongmingQ, BingL, XiaojieL (2011) Neuroprotective effect of sophocarpine against transient focal cerebral ischemia via down-regulation of the acid-sensing ion channel 1 in rats. Brain Res1382, 245–251.
61.
CadiouH, StuderM, JonesNG, SmithES, BallardA, McMahonSB, McNaughtonPA (2007) Modulation of acid-sensing ion channel activity by nitric oxide. J Neurosci27, 13251–13260.
62.
SmithES, CadiouH, McNaughtonPA (2007) Arachidonic acid potentiates acid-sensing ion channels in rat sensory neurons by a direct action. Neuroscience145, 686–698.
63.
DuanB, WangYZ, YangT, ChuXP, YuY, HuangY, CaoH, HansenJ, SimonRP, ZhuMX, XiongZG, XuTL (2011) Extracellular spermine exacerbates ischemic neuronal injury through sensitization of ASIC1a channels to extracellular acidosis. J Neurosci31, 2101–2112.
64.
TikhonovaTB, NagaevaEI, BaryginOI, PotapievaNN, BolshakovKV, TikhonovDB (2015) Monoamine NMDA receptor channel blockers inhibit and potentiate native and recombinant proton-gated ion channels. Neuropharmacology89, 1–10.
65.
DuringMJ, SymesCW, LawlorPA, LinJ, DunningJ, FitzsimonsHL, PoulsenD, LeoneP, XuR, DickerBL, LipskiJ, YoungD (2000) An oral vaccine against NMDAR1 with efficacy in experimental stroke and epilepsy. Science287, 1453–1460.
66.
SchehrRS (1996) New treatments for acute stroke. Nat Biotechnol14, 1549–1554.
67.
GilliesRJ, RaghunandN, Garcia-MartinML, GatenbyRA (2004) pH imaging. A review of pH measurement methods and applications in cancers. IEEE Eng Med Biol Mag23, 57–64.
68.
MandalPK, AkolkarH, TripathiM (2012) Mapping of hippocampal pH and neumicals from in vivo multi-voxel 31P study in healthy normal young male/female, mild cognitive impairment, and Alzheimer’s disease. J Alzheimers Dis31(Suppl 3), S75–S86roche.
69.
KettunenMI, GrohnOH, SilvennoinenMJ, PenttonenM, KauppinenRA (2002) Effects of intracellular pH, blood, and tissue oxygen tension on T1rho relaxation in rat brain. Magn Reson Med48, 470–477.
70.
JokivarsiKT, HiltunenY, GrohnH, TuunanenP, GrohnOH, KauppinenRA (2010) Estimation of the onset time of cerebral ischemia using T1rho and T2 MRI in rats. Stroke41, 2335–2340.
71.
MagnottaVA, HeoHY, DlouhyBJ, DahdalehNS, FollmerRL, ThedensDR, WelshMJ, WemmieJA (2012) Detecting activity-evoked pH changes in human brain. Proc Natl Acad Sci U S A109, 8270–8273.
PontoL, SchultzS, MendaY, ArndtS, MagnottaV (2016) Alzheimer’s pathology and the pH-sensitive marker T1rho MRI. J Nucl Med57, 129.
74.
BaerJE, JonesCB, SpitzerSA, RussoHF (1967) The potassium-sparing and natriuretic activity of N-amidino-3,5-diamino-6-chloropyrazinecarboxamide hydrochloride dihydrate (amiloride hydrochloride). J Pharmacol Exp Ther157, 472–485.
75.
O’NeilRG, BoulpaepEL (1979) Effect of amiloride on the apical cell membrane cation channels of a sodium-absorbing, potassium-secreting renal epithelium. J Membr Biol50, 365–387.
76.
EscoubasL, FloryF, LemarchandF, DuringA, RouxL (2000) Enhanced diffraction efficiency of gratings in multilayers. Opt Lett25, 194–196.
77.
DiochotS, BaronA, RashLD, DevalE, EscoubasP, ScarzelloS, SalinasM, LazdunskiM (2004) A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J23, 1516–1525.
78.
DiochotS, BaronA, SalinasM, DouguetD, ScarzelloS, Dabert-GayAS, DebayleD, FriendV, AllouiA, LazdunskiM, LinguegliaE (2012) Black mamba venom peptides target acid-sensing ion channels to abolish pain. Nature490, 552–555.
79.
BaezA, SalcedaE, FloM, GranaM, FernandezC, VegaR, SotoE (2015) alpha-Dendrotoxin inhibits the ASIC current in dorsal root ganglion neurons from rat. Neurosci Lett606, 42–47.
80.
BohlenCJ, CheslerAT, Sharif-NaeiniR, MedzihradszkyKF, ZhouS, KingD, SanchezEE, BurlingameAL, BasbaumAI, JuliusD (2011) A heteromeric Texas coral snake toxin targets acid-sensing ion channels to produce pain. Nature479, 410–414.
