The Acid-sensitive Ionic Channel Subunit ASIC and the Mammalian Degenerin MDEG Form a Heteromultimeric H+-gated Na+ Channel with Novel Properties

Abstract

Proton-gated cation channels are acid sensors that are present in both sensory neurons and in neurons of the central nervous system. One of these acid-sensing ion channels (ASIC) has been recently cloned. This paper shows that ASIC and the mammalian degenerin MDEG, which are colocalized in the same brain regions, can directly associate with each other. Immunoprecipitation of MDEG causes coprecipitation of ASIC. Moreover, coexpression of ASIC and MDEG subunits in Xenopus oocytes generates an amiloride-sensitive H ؉ -gated Na ؉ channel with novel properties (different kinetics, ionic selectivity, and pH sensitivity). In addition, coexpression of MDEG with mutants of the ASIC subunit can create constitutively active channels that become completely nonselective for Na ؉ versus K ؉ and H ؉ -gated channels that have a drastically altered pH sensitivity compared with MDEG. These data clearly show that ASIC and MDEG can form heteromultimeric assemblies with novel properties. Heteromultimeric assembly is probably used for creating a diversity of H ؉ -gated cation channels acting as neuronal acid sensors in different pH ranges.H ϩ -gated cation channels are ligand-gated ion channels activated by the simplest possible ligand, the proton. In nociceptive neurons those channels are thought to be responsible for the sensation of pain that accompanies tissue acidosis (1-3), particularly during inflammation and ischemic conditions. H ϩ -gated cation channels are also present in neurons of the central nervous system (2), where their physiological role remains to be established. We have recently cloned a proton-gated cation channel (ASIC, acid sensing ion channel 1) (4). The closest structural homologue of ASIC is MDEG (5, 6). MDEG is a mammalian degenerin. Upon the same mutations that in Caenorhabditis elegans degenerins induce degeneration of specific neurons (7,8), MDEG can also acquire constitutive Na ϩ channel activity that becomes toxic for the cells in which it is expressed (5). In addition, native MDEG also behaves as a H ϩ -gated Na ϩ channel. The variety of H ϩ -gated cation channels with different ion selectivities, pH dependencies, and kinetics described in sensory neurons (1, 9, 10), as well as in neurons of the central nervous system (2), suggests that ASIC and MDEG are probably only the first two members of this novel ion channel family and that other genes for new H ϩ -activated Na ϩ channels remain to be discovered. However, the existence of different genes is probably only one of the ways used to create a diversity of H ϩ -gated cation channels. Many other types of ion channels are known to form heteromultimers of structurally related subunits, resulting in the assembly of channels with novel properties (11). Furthermore, other structural homologues of the ASIC and MDEG channels, such as the epithelial amiloride-sensitive Na ϩ channel (12-18) and the degenerins of the nematode C. elegans, which are believed to be mechanosensitive channels (19 -21), require heteromultimeric subunit assembly for their function. All...

Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases

“…It reversibly inhibits the ASIC currents with an IC 50 of 10 -50 μM [10,13,24,28,42]. Similar to its effect on the ASIC currents, amiloride inhibits acidinduced increase of [Ca 2+ ] i and membrane depolarization [10,12,43,44].…”

Identification, functional expression and chromosomal localisation of a sustained human proton‐gated cation channel

“…The perception of pain during tissue acidosis is thought to be caused by the opening of protongated cation channels present in sensory neurones [3,5,6]. Recently, the first members of the proton-gated cation channel family were cloned (ASICI [7], ASIC2 [MDEGI] [8], and ASIC3 [rDRASIC] [9]) and it was demonstrated that heteromultimeric assembly of different subunits further increases the variety of H+-gated cation channels ( [8,10] reviewed in [11]). ASIC1 and ASIC2 (MDEG1) are expressed in neurones of the CNS and in sensory neurones.…”

Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a

“…In addition to ASIC1a homomultimers, hippocampal neurons also express ASIC2, and some of the H ϩ -activated current is produced by ASIC1a͞2a heteromultimeric channels (3,5,(7)(8)(9)(10)34). Therefore, we also tested these channels expressed in COS-7 cells.…”

“…In cultured neurons, recombinant ASIC1a can be found on the cell body, but it also localizes to dendrites and is present at synapses (6). In central neurons, ASIC1a forms both homomultimers and heteromultimers with ASIC2a (7)(8)(9)(10). These complexes generate cation channels that are activated by a fall in the extracellular pH.…”