Molecular and Functional Characterization of Acid-sensing Ion Channel (ASIC) 1b

Abstract

Acid-sensing ion channels (ASICs) are activated by extracellular protons and are involved in neurotransmission in the central nervous system, in pain perception, as well as in mechanotransduction. Six different ASIC subunits have been cloned to date, which are encoded by four genes (ASIC1-ASIC4). Proton-gated currents have been described in isolated neurons from sensory ganglia as well as from central nervous system. However, it is largely unclear which of the cloned ASIC subunits underlie these native proton-gated currents. Recently, a splice variant, ASIC-␤, has been described for ASIC1a. In this variant about one-third of the protein is exchanged at the N terminus. Here we show that ASIC-␤ has a longer N terminus than previously reported, extending the sequence divergence between ASIC1a and this new variant (ASIC1b). We investigated in detail kinetic and selectivity properties of ASIC1b in comparison to ASIC1a. Kinetics is similar for ASIC1b and ASIC1a. Ca 2؉ permeability of ASIC1a is low, whereas ASIC1b is impermeable to Ca 2؉ . Currents through ASIC1a resemble currents, which have been described in sensory and central neurons, whereas the significance of ASIC1b remains to be established. Moreover, we show that a pre-transmembrane 1 domain controls the permeability to divalent cations in ASIC1, contributing to our understanding of the pore structure of these channels.

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

“…ASIC1b (ASIC1β) is a splice variant of ASIC1a with restricted expression in sensory neurons [24]. Homomeric ASIC1b channels respond to pH o drop with a similar transient current and a pH 0.5 of ∼5.9 [24,25]. Unlike ASIC1a, homomeric ASIC1b channels do not show Ca 2+ permeability.…”

The acid-sensing ion channel 2 (ASIC2) of ciliated cells in the developing rat nasal septum

“…Among them, ASIC1 and ASIC2 have spliced variants. The ASIC1 gene spliced variants are ASIC1a and ASIC1b, and ASIC2 spliced variants are ASIC2a and ASIC2b (Lingueglia et al, 1997;Waldmann et al, 1997;Chen et al, 1998;Bassler et al, 2001). No spliced variants of ASIC3 or ASIC4 have been detected.…”

Hypercapnic Acidosis Impairs Plasma Membrane Wound Resealing in Ventilator-injured Lungs

“…CO 2 generates H ϩ ions, which react with titratable groups in certain amino acids and/or interacts directly with free amine groups in proteins to form carbamate residues (14)(15)(16). CO 2 -dependent effects on the generation of reactive oxygen species and reactive nitrogen species as well as effects on ion channel conductivity have all been considered (17,18).…”