ASIC and ENaC type sodium channels: conformational states and the structures of the ion selectivity filters

Abstract

The acid-sensing ion channels (ASICs) and epithelial sodium channels (ENaC) are members of a superfamily of channels that play critical roles in mechanosensation, chemosensation, nociception, and regulation of blood volume and pressure. These channels look and function like a tripartite funnel that directs the flow of Na + ions into the cytoplasm via the channel pore in the membrane. The subunits that form these channels share a common structure with two transmembrane segments (TM1 and TM2) and a large extracellular part. In most vertebrates, there are five paralogous genes that code for ASICs (ASIC1-ASIC5), and four for ENaC subunits alpha, beta, gamma, and delta (a, b, c, and d). While ASICs can form functional channels as a homo-or heterotrimer, ENaC functions as an obligate heterotrimer composed of a-b-c or b-c-d subunits. The structure of ASIC has been determined in several conformations, including desensitized and open states. This review presents a comparison of the structures of these states using easy-to-understand molecular models of the full complex, the central tunnel that includes an outer vestibule, the channel pore, and ion selectivity filter. The differences in the secondary, tertiary, and quaternary structures of the states are summarized to pinpoint the conformational changes responsible for channel opening. Results of site-directed mutagenesis studies of ENaC subunits are examined in light of ASIC1 models. Based on these comparisons, a molecular model for the selectivity filter of ENaC is built by in silico mutagenesis of an ASIC1 structure. These models suggest that Na + ions pass through the filter in a hydrated state.

Arginyl dipeptides increase the frequency of NaCl-elicited responses via epithelial sodium channel alpha and delta subunits in cultured human fungiform taste papillae cells

“…Among them, the subunits α (or δ), β and γ, which are highly conserved in all vertebrates, are essential for the assembly of functional channels. The δ ENaC subunit exhibits maximal activity when co-expressed with β and γ subunits 33, 34 . Both pharmacological and siRNA studies indicated that AR increased NaCl-induced responses via the amiloride-sensitive pathways (Figs 4a–e, 7a–f).…”

“…It has been reported that ENaC has two major states: open and closed. Hormones, proteases, ions, and signal transduction systems exert their regulatory role on ENaC activity by influencing directly or indirectly the probability of ENaC being in the open state, as well as the number of ENaC receptors in the apical membrane 33 . The mechanism by which AR affects the activity of ENaC remains to be investigated.…”

Piezo channels and GsMTx4: Two milestones in our understanding of excitatory mechanosensitive channels and their role in pathology

“…Sound induced vibrations lead to motion between adjacent cilia and activation of the tethered channels. The family of DEG/ENaC/ASIC channels are MSCs present in both non-specialized and specialized mechanosensory cells [24, 25], and are gated by movement of their extracellular domains [26] that are associated with the ECM [27]. This connection to the ECM is disrupted during patch formation which is likely why these channels do not show mechanosensitivity in patches [25, 28].…”

Synaptic signals mediated by protons and acid‐sensing ion channels

“…Center: Schematic view of one ASIC subunit with domains labeled according to the X‐ray structure of Baconguis et al, (), adapted from Kellenberger and Schild () and binding site of PcTx1 and Amiloride. Top right: top view of a trimeric ASIC channel, adapted from Hanukoglu ()…”