doi: 10.1161/CIRCRESAHA.107.164442
© 2007 American Heart Association, Inc.
Editorials |
An ASIC Channel for Acid Chemotransduction
From the Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina e IBGM, Universidad de Valladolid y CSIC, Valladolid, Spain.
Correspondence to Dr Teresa Perez-Garcia, Universidad de Valladolid, Department of Biochemistry and Physiology, Facultad de Medicina, c/ Ramon y Cajal 7, Valladolid 47005, Spain. E-mail tperez{at}ibgm.uva.es
See related article, pages 1009–1019
Key Words: carotid body chemoreceptors • CO2/pH sensing • ion channels
Spontaneous breathing requires feedback controls in which detection of blood gas and pH are critical. While O2 detection is performed by pheripheral chemoreceptors, CO2/pH-sensitive chemoreceptors are in the carotid bodies (CBs), but major sites are also within the brain (the central chemoreceptors [CCR]). CO2/pH signals are related to the acid-base status of the blood and reflect the adequacy of breathing to metabolism. Small changes in CO2/pH can affect breathing, so that a rise in PCO2 as small as 1 mm Hg produces an evident change in ventilation.1 Such a high CO2 sensitivity relies in the inherent properties of CO2/pH-sensing molecules present both in CB and CCR cells, as shown in several recent studies on CO2/pH sensing ion channels and receptors.2,3 Functional properties of most proteins can be regulated by changes in pH, as this would only require 1 or a few titratable residues of the molecule, whose protonation can lead to conformation changes that translate into changes in activity. However, to define whether those molecules have a relevant role in CO2/pH chemoreception, some more criteria should be met, including their range of pH sensitivity, their location in chemoreceptor cells, and their functional contribution to the integrated chemoreceptor response. In this regard, the molecular characterization of pH-sensitive channels and transporters has progressed considerably within the last years, but conclusive evidences of their contribution to acid chemotransduction are not so well established for many of them. The main reason for this delay is the fact that the identity of the primary sensory cells constituting CCRs and of their neuronal networks remains elusive. In vitro, neurons from many brain locations are excited or inhibited by CO2/pH changes, but it has been difficult to link this neuronal chemosensitivity to chemoreception in vivo. Moreover, in addition to chemosensitive neurons, CCRs sites may also contain neurons with other integrative functions that are not clearly distinct from chemosensitive ones in their morphological or functional properties, making their experimental study difficult.
Several members of the inward rectifier K+ (Kir) channels are among these pH-sensing molecules, as they have been reported to be highly sensitive to intra or extracellular pH (pHi and pHo) in the physiological range and also regulated by moderate changes in CO2 levels (see2,3 for review). Another group of channels involved in pH signaling are the members of the 2-pore domain K+ channels, that are also modulated by changes in pHi or pHo,.4 Among them, TASK-1 channels have been shown to contribute to chemosensitivity of both brain stem neurons5 and rat CB chemoreceptor cells.6 Other ion channels modulated by CO2/pH changes include voltage-activated K+ channels, L-type Ca2+ channels, pacemaker HCN channels, TRP channels, and the family of acid-sensing ion channels (ASICs).3 These amiloride-sensitive non–voltage-dependent cationic channels were originally described as transducers of pH signals in pheripheral sensory neurons. They have been identified afterward in a large number of central and pheripheral neurons, where they show a striking functional diversity: they modulate a wide range of sensory functions including perception of touch, taste, temperature, and pain, but they are also involved in neuronal plasticity, hence contributing to learning and memory.7,8
The study performed by Tan et al9 in this issue of Circulation Research provides a new biological function to ASICs channels by demonstrating their involvement in acidic-stimuli chemotransduction in CB chemoreceptors. They report the expression of ASIC-1 and ASIC-3 in chemoreceptor cells and their contribution to cell excitability on changes in pHo. The choice of this preparation, a chemosensitive organ with a well defined structure and function (as opposed to CCRs), allows them to gain insight into the possible physiological role of ASICs channels as chemoreceptor molecules.
The CB chemoreceptor cells are the sensory receptors for hypoxia, hypercapnia, and acidosis.10,11 In the case of low PO2, the depolarizing receptor potential arises primarily from the inhibition of several classes of K+ conductances, which vary among different species.12–14 This depolarization leads to calcium entry through voltage-dependent Ca2+ channels and release of neurotransmitters that excite the afferent nerve terminals. The transduction mechanisms for hypercapnic and acidic stimuli in CB chemoreceptor cells have received less attention, but as these cells are easier to identify and isolate, studies on the cellular mechanisms of CO2/pH chemoreception preceded similar studies in CCRs. There is strong evidence that these stimuli also produce inhibition of several ion channels.15,16 The effects of hypercapnia have long been considered to be secondary to acidification of pHi,17 which would be the trigger of K+ channel inhibition, leading to membrane depolarization and voltage-gated Ca2+ entry.18 Several studies demonstrating that the blockade of voltage-dependent Ca2+ channels inhibits chemoreceptor responses to hypercapnia19,20 confirm their involvement in CO2/pH chemotransduction in the CB. Although species-related differences in the molecular identity of the mechanisms involved have been reported, this general scheme holds true for several preparations in which CO2/pH chemotransduction has been explored, being the rat CB the one studied in more detail.
In the rat CB, the K+ channel modulated by pHi was initially suggested to be the maxiK (KCa) channel. However, the pH sensitivity of this channel was very limited15 and its pharmacological blockade did not depolarize chemoreceptor cells, indicating that KCa channel inhibition was not the trigger of the CO2/pH chemotransduction cascade.12 Ulterior studies demonstrating the presence of TASK-1 channels in rat CB and their inhibition by a fall in pHo led to the proposal that both pHi and pHo will participate in the response to acidic stimuli.6 In addition to these K+ channels, a recent study demonstrated the presence in rat CB cells of an inwardly-rectifier Cl– current activated by decreasing pHo.21 This current was proposed to participate in intracellular acidification and membrane depolarization during acidic challenge. Extracellular acidosis, by increasing Cl– conductance and decreasing TASK channel conductance, will result in plasma membrane depolarization. Moreover, the increased efflux of chloride by activation of this channel would led to CO3H– efflux through the Cl–/CO3H– transporter present in chemoreceptor cells,10 resulting in a fall in pHi. In this way this anion current could also contribute to the adaptation of pHi to pHo. However, to confirm these hypotheses, the study of the contribution of Cl– channels to CB chemoreception warrants further investigation.
The present article9 adds a new candidate for acid chemotransduction, ASICs channels, that would be functioning best as pHo sensors, as demonstrated by their lactate sensitivity. The enhancement of currents through ASICs channels in the presence of lactate has been demonstrated to be mediated by the ability of lactate to quelate extracellular Ca2+. In an elegant series of experiments, Immke and McCleskey22 conclude that H+ open ASICs by accelerating the release of Ca2+ from a high affinity binding site on the external side of the pore, suggesting that this relief of Ca2+ blockade is in fact the essence of ASICs gating by H+. This mechanism of activation may contribute to chemoreceptor selectivity, making ASICs channels more responsive to metabolic acidosis, and thus participating in the ventilatory adaptation during exercise.10
The emerging picture from these results suggests that, as in the case of other sensory modalities, there is a parallel processing for CO2/pH detection in CB chemoreceptors, involving multiple sensors (Figure) which could be expressed in a single cell or in different cell populations. By having different preferred stimuli (respiratory versus metabolic acidosis) and different sensitivity range, they would contribute to generate adaptive respiratory responses over a broader range of CO2/pH changes. In response to hypercapnia or acidosis, multiple signals are generated. Both pHi and pHo could serve as the immediate stimulus for chemoreceptors (in fact they may operate simultaneously), and even CO2 itself could be sensed independently of pHi changes.23 In this regard, it should be noted that none of the identified sensors (Cl–, TASK-1, and ASICs channels) explain CB chemoreceptors response to isohydric hypercapnia, where there are not associated pHo changes. Further studies along this line of research are needed to complete the identification of the molecular mechanisms involved, and to explore the possibility of additive or synergistic effects of CO2/pH changes on CB chemoreceptors acting on different molecular targets.
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Acknowledgments |
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Sources of Funding
This work was supported by Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III grants R006/009 (Red Heracles) and PI041044 (JRLL), Ministerio de Educación y Ciencia grant BFU2004-05551 (to M.T.P.G.) and Junta de Castilla y León grant VA011C05.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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 Top References |
|---|
- Feldman JL, Mitchell GS, Nattie EE. Breathing: rhythmicity, plasticity, chemosensitivity. Annu Rev Neurosc. 2003; 26: 239–266.[CrossRef][Medline] [Order article via Infotrieve]
- Putnam RW, Filosa JA, Ritucci NA. Cellular mechanisms involved in CO(2) and acid signaling in chemosensitive neurons. Am J Physiol Cell Physiol. 2004; 287: C1493–C1526.
[Abstract/Free Full Text] - Jiang C, Rojas A, Wang R, Wang X. CO2 central chemosensitivity: why are there so many sensing molecules? Respir Physiol Neurobiol. 2005; 145: 115–126.[CrossRef][Medline] [Order article via Infotrieve]
- Lesage F, Lazdunski M. Molecular and functional properties of two-pore-domain potassium channels. Am J Physiol Renal Physiol. 2000; 279: F793–F801.
[Abstract/Free Full Text] - Bayliss DA, Sirois JE, Talley EM. The TASK Family: Two-Pore Domain Background K+ Channels. Mol Interv. 2003; 3: 205–219.
[Abstract/Free Full Text] - Buckler KJ, Williams BA, Honore E. An oxygen-, acid- and anaesthetic-sensitive TASK-like background potassium channel in rat arterial chemoreceptor cells. J Physiol. 2000; 525 Pt 1: 135–142.
[Abstract/Free Full Text] - Bianchi L, Driscoll M. Protons at the gate: DEG/ENaC ion channels help us feel and remember. Neuron. 2002; 34: 337–340.[CrossRef][Medline] [Order article via Infotrieve]
- Wemmie JA, Price MP, Welsh MJ. Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci. 2006; 29: 578–586.[CrossRef][Medline] [Order article via Infotrieve]
- Tan ZY, Lu Y, Whiteis CA, Benson CJ, Chapleau MW, Abboud FM. Acid-sensing ion channels contribute to transduction of extracellular acidosis in rat carotid body glomus cells. Circ Res. 2007; 101: 1009–1019.
[Abstract/Free Full Text] - Gonzalez C, Almaraz L, Obeso A, Rigual R. Carotid body chemoreceptors: from natural stimuli to sensory discharges. Physiol Rev. 1994; 74: 829–898.
[Free Full Text] - Peers C, Buckler KJ. Transduction of Chemostimuli by the Type I Carotid Body Cell. J Membrane Biol. 1995; 144: 1–9.[Medline] [Order article via Infotrieve]
- Buckler KJ. TASK-like potassium channels and oxygen sensing in the carotid body. Respir Physiol Neurobiol. 2007; 157: 55–64.[CrossRef][Medline] [Order article via Infotrieve]
- Peers C, Wyatt CN. The role of maxiK channels in carotid body chemotransduction. Respir Physiol Neurobiol. 2007; 157: 75–82.[CrossRef][Medline] [Order article via Infotrieve]
- Lopez-Lopez JR, Perez-Garcia MT. Oxygen sensitive Kv channels in the carotid body. Respir Physiol Neurobiol. 2007; 157: 65–74.[CrossRef][Medline] [Order article via Infotrieve]
- Peers C, Green FK. Inhibition of Ca(2+)-activated K+ currents by intracellular acidosis in isolated type I cells of the neonatal rat carotid body. J Physiol. 1991; 437: 589–602.
[Abstract/Free Full Text] - Stea A, Alexander SA, Nurse CA. Effects of pHi and pHe on membrane currents recorded with the perforated-patch method from cultured chemoreceptors of the rat carotid body. Brain Res. 1991; 567: 83–90.[CrossRef][Medline] [Order article via Infotrieve]
- Buckler KJ, Vaughan-Jones RD, Peers C, Lagadic-Gossmann D, Nye PC. Effects of extracellular pH, PCO2 and HCO3– on intracellular pH in isolated type-I cells of the neonatal rat carotid body. J Physiol. 1991; 444: 703–721.
[Abstract/Free Full Text] - Buckler KJ, Vaughan Jones RD. Effects of hypercapnia on membrane potential and intracellular calcium in rat carotid body type I cells. J Physiol. 1994; 478: 157–171.[Medline] [Order article via Infotrieve]
- Roy A, Rozanov C, Iturriaga R, Mokashi A, Lahiri S. Acid-sensing by carotid body is inhibited by blockers of voltage- sensitive Ca2+ channels. Brain Res. 1997; 769: 396–399.[CrossRef][Medline] [Order article via Infotrieve]
- Rocher A, Geijo-Barrientos E, Caceres AI, Rigual R, Gonzalez C, Almaraz L. Role of voltage-dependent calcium channels in stimulus-secretion coupling in rabbit carotid body chemoreceptor cells. J Physiol. 2005; 562: 407–420.
[Abstract/Free Full Text] - Petheo GL, Molnar Z, Roka A, Makara JK, Spat A. A pH-sensitive chloride current in the chemoreceptor cell of rat carotid body. J Physiol. 2001; 535: 95–106.
[Abstract/Free Full Text] - Immke DC, McCleskey EW. Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade. Neuron. 2003; 37: 75–84.[CrossRef][Medline] [Order article via Infotrieve]
- Summers BA, Overholt JL, Prabhakar NR. CO(2) and pH independently modulate L-type Ca(2+) current in rabbit carotid body glomus cells. J Neurophysiol. 2002; 88: 604–612.
[Abstract/Free Full Text]
Related Article:
- Acid-Sensing Ion Channels Contribute to Transduction of Extracellular Acidosis in Rat Carotid Body Glomus Cells
- Zhi-Yong Tan, Yongjun Lu, Carol A. Whiteis, Christopher J. Benson, Mark W. Chapleau, and Francois M. Abboud
Circ. Res. 2007 101: 1009-1019.[Abstract] [Full Text] [PDF]
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