A receptor for protons in the nerve cell membrane

Krishtal, O. A.; Pidoplichko, V I

doi:10.1016/0306-4522(80)90149-9

Cited by 479 publications

(295 citation statements)

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“…T ransient proton-activated currents in peripheral sensory neurons were first described more than 20 years ago (1). These currents were thought to mediate acid-induced pain sensation (2).…”

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confidence: 99%

Heteromultimers of DEG/ENaC subunits form H ⁺ -gated channels in mouse sensory neurons

Benson

Xie

Wemmie

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

337

370

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Acidic extracellular solution activates transient H+-gated currents in dorsal root ganglion (DRG) neurons. The biophysical properties of three degenerin/epithelial sodium (DEG/ENaC) channel subunits (BNC1, ASIC, and DRASIC), and their expression in DRG, suggest that they might underlie these H+-gated currents and function as sensory transducers. However, it is uncertain which of these DEG/ENaC subunits generate the currents, and whether they function as homomultimers or heteromultimers. We found that the biophysical properties of transient H+-gated currents from medium to large mouse DRG neurons differed from BNC1, ASIC, or DRASIC expressed individually, but were reproduced by coexpression of the subunits together. To test the contribution of each subunit, we studied DRG from three strains of mice, each bearing a targeted disruption of BNC1, ASIC, or DRASIC. Deletion of any one subunit did not abolish H+-gated currents, but altered currents in a manner consistent with heteromultimerization of the two remaining subunits. These data indicate that combinations of two or more DEG/ENaC subunits coassemble as heteromultimers to generate transient H+-gated currents in mouse DRG neurons

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“…T ransient proton-activated currents in peripheral sensory neurons were first described more than 20 years ago (1). These currents were thought to mediate acid-induced pain sensation (2).…”

mentioning

confidence: 99%

Heteromultimers of DEG/ENaC subunits form H ⁺ -gated channels in mouse sensory neurons

Benson

Xie

Wemmie

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

337

370

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“…Acid-sensing ion channels select Na ϩ over other ions (13,28), but prolonged application of very low pH (Յ 5.0) evokes a distinctly different current in some sensory neurons. This current is sustained, is carried equally by various monovalent cations, and is not blocked by amiloride (29).…”

Section: Resultsmentioning

confidence: 99%

“…This behavior of the currents identifies them as being carried by acid-sensing ion channels (ASICs) and distinguishes them from another type of proton-gated channel, vanilloid receptors. Krishtal's group identified ASICs as several kinetically distinct, Na ϩ -selective, Ca 2ϩ -permeant currents in sensory neurons that are evoked by lowered pH and are blocked by amiloride (13)(14)(15)(16)). Lazdunski's group found that the currents are carried by a protonsensitive subfamily of channels within the larger family of epithelial Na ϩ channels and degenerins of Caenorhabditis elegans (17).…”

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confidence: 99%

From the Cover: Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons

Sutherland¹

2000

Proceedings of the National Academy of Sciences

105

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Cardiac afferents are sensory neurons that mediate angina, pain that occurs when the heart receives insufficient blood supply for its metabolic demand (ischemia). These neurons display enormous acid-evoked depolarizing currents, and they fire action potentials in response to extracellular acidification that accompanies myocardial ischemia. Here we show that acid-sensing ion channel 3 (ASIC3), but no other known acid-sensing ion channel, reproduces the functional features of the channel that underlies the large acid-evoked current in cardiac afferents. ASIC3 and the native channel are both especially sensitive to pH, interact similarly with Ca 2؉ , and gate rapidly between closed, open, and desensitized states. Particularly important is the ability of ASIC3 and the native channel to open at pH 7, a value reached in the first few minutes of a heart attack. The steep activation curve suggests that the channel opens when four protons bind. We propose that ASIC3, a member of the degenerin channel (of Caenorhabditis elegans)͞ epithelial sodium channel family of ion channels, is the sensor of myocardial acidity that triggers cardiac pain, and that it might be a useful pharmaceutical target for treating angina.

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“…Drugs and Krebs solutions were applied to the neurones by a rapid perfusion system consisting of a multibarrelled pipette made from Quad glass (Q-tube, Clarks Electromedical). The concentration-response relation for AMPA was determined with a U-tube perfusion system for drug application (Krishtal & Pidoplichko, 1980;Fenwick et al, 1982). The U-or Q-tubes were placed within 300 pm of the cell under study.…”

Section: Whole-cell Recording From Cultured Neuronesmentioning

confidence: 99%

Thiocyanate ions selectively antagonize AMPA‐evoked responses in Xenopus laevis oocytes microinjected with rat brain mRNA

Bowie

Smart

1993

British J Pharmacology

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1 Responses to kainate (KA), willardiine and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were recorded from rat brain mRNA-injected Xenopus laevis oocytes by use of a two-electrode voltage clamp.2 Thiocyanate (SCN-; 50jM-4mM) ions reversibly and selectively inhibited the membrane current responses to AMPA in a non-competitive manner without affecting KA or willardiine-induced responses.3 The inhibition of AMPA-induced responses by SCN-was dependent on the SCN-concentration with an estimated IC50 of 1 mm. The antagonism was not dependent on the AMPA concentration. 4 The response to a high concentration of AMPA (100-200I1M) exhibited a peak inward current which declined to a steady-state. SCN-inhibited the steady-state current more than the peak response. The inhibition was unaffected by prior incubation with concanavalin-A (Con-A; 10#M). 5 Responses to KA were antagonized by AMPA in a competitive manner, suggesting that both agonists may activate a common receptor-channel complex. This interaction between two non-NMDA agonists was not affected by the SCN-induced inhibition of the AMPA response. 6 AMPA-induced responses recorded from large cultured cerebellar neurones by whole-cell recording were also inhibited by SCN-in a non-competitive manner. The AMPA-induced peak current was less affected than the steady-state response. 7 We conclude that SCN-can inhibit the response to AMPA in expressed non-NMDA receptors in Xenopus oocytes and also in native receptors in cultured cerebellar neurones. One possible mechanism of action for SCN-inhibition of responses to AMPA may involve a Con-A-insensitive, non-NMDA receptor-mediated desensitization.

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A receptor for protons in the nerve cell membrane

Cited by 479 publications

References 1 publication

Heteromultimers of DEG/ENaC subunits form H ⁺ -gated channels in mouse sensory neurons

Heteromultimers of DEG/ENaC subunits form H ⁺ -gated channels in mouse sensory neurons

From the Cover: Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons

Thiocyanate ions selectively antagonize AMPA‐evoked responses in Xenopus laevis oocytes microinjected with rat brain mRNA

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A receptor for protons in the nerve cell membrane

Cited by 479 publications

References 1 publication

Heteromultimers of DEG/ENaC subunits form H + -gated channels in mouse sensory neurons

Heteromultimers of DEG/ENaC subunits form H + -gated channels in mouse sensory neurons

From the Cover: Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons

Thiocyanate ions selectively antagonize AMPA‐evoked responses in Xenopus laevis oocytes microinjected with rat brain mRNA

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Heteromultimers of DEG/ENaC subunits form H ⁺ -gated channels in mouse sensory neurons

Heteromultimers of DEG/ENaC subunits form H ⁺ -gated channels in mouse sensory neurons