Regulation of ion transport from within ion transit pathways

Abstract

All cells must control the activities of their ion channels and transporters to maintain physiologically appropriate gradients of solutes and ions. The complexity of underlying regulatory mechanisms is staggering, as exemplified by insulin regulation of transporter trafficking. Simpler strategies occur in single-cell organisms, where subsets of transporters act as solute sensors to regulate expression of their active homologues. This Viewpoint highlights still simpler mechanisms by which Na transporters use their own transport sites as sensors for regulation. The underlying principle is inherent to Na/K pumps in which aspartate phosphorylation and dephosphorylation are controlled by occupation of transport sites for Na and K, respectively. By this same principle, Na binding to transport sites can control intrinsic inactivation reactions that are in turn modified by extrinsic signaling factors. Cardiac Na/Ca exchangers (NCX1s) and Na/K pumps are the best examples. Inactivation of NCX1 occurs when cytoplasmic Na sites are fully occupied and is regulated by lipid signaling. Inactivation of cardiac Na/K pumps occurs when cytoplasmic Na-binding sites are not fully occupied, and inactivation is in turn regulated by Ca signaling. Potentially, Na/H exchangers (NHEs) and epithelial Na channels (ENaCs) are regulated similarly. Extracellular protons and cytoplasmic Na ions oppose secondary activation of NHEs by cytoplasmic protons. ENaCs undergo inactivation as cytoplasmic Na rises, and small diffusible molecules of an unidentified nature are likely involved. Multiple other ion channels have recently been shown to be regulated by transiting ions, thereby underscoring that ion permeation and channel gating need not be independent processes.

FXYD protein isoforms differentially modulate human Na/K pump function

“…The importance of studies to describe in detail the slow transitions that depend on the presence of transported ions is highlighted by the recent observation of a Na + i depletion-triggered inactivated state described by Hilgemann (2020b) . The appearance of the slow activation phase in patches, just like the entrance into the inactivated state in whole-cell experiments, is dramatically influenced by the presence of competing K + i ( Lu and Hilgemann, 2017 ).…”

“…The appearance of the slow activation phase in patches, just like the entrance into the inactivated state in whole-cell experiments, is dramatically influenced by the presence of competing K + i ( Lu and Hilgemann, 2017 ). Therefore, it is possible that the slow ATP-activation phase we describe here represents the inactive state entered by Na/K pumps when the Na + i concentration is reduced in whole-cell patch-clamp experiments with ventricular myocytes ( Hilgemann, 2020b ; Lu and Hilgemann, 2017 ). If this is the case, the changes in apparent ion selectivity of intracellular-facing pumps induced by FXYD proteins that we describe here would have profound consequences on Na/K pump activity.…”

Sodium Fluctuations in Astroglia and Their Potential Impact on Astrocyte Function

“…In neural (radial glia like) stem cells of the subependymal zone, Na + influx through epithelial sodium channels (ENaC) stimulated Ca 2+ signaling, presumably through reverse NCX, contributing to the regulation of their proliferation (Petrik et al, 2018). Of note, and similar to Na + -dependent regulation of NKA activity described above, NCX was proposed to be subject to a secondary Na + -dependent inactivation following Na + binding to its inward facing transport sites in cardiac myocytes (Hilgemann, 2020). Such Na + -dependent inactivation of NCX in astrocytes could reduce Ca 2+ influx upon its reversal, a process which might be relevant to dampen Ca 2+ overload under pathological conditions.…”

“…It has long been established that the pump cycle of the NKA is dependent on binding of Na + ; once all three binding sites for Na + are occupied, the transporter undergoes conformational changes that regulate the cleavage of ATP (Clausen et al, 2017). In addition, mainly based on work on cardiac myocytes, a secondary activation of NKA by Na + was proposed, complemented by a so-called "Na + -deficiency inactivation" that may serve to maintain the pumps in a "reserve state" when not needed (Hilgemann, 2020).…”

Electro-Steric Mechanism of CLC-2 Chloride Channel Activation

“…Thus, it is likely that a 582 mechanism entailing electro--steric gating is present in all CLC Cl -channels. In addition to CLC Cl --583 channels, the K2P K + channels that lack a voltage sensor domain also display voltage 584 dependence due to the movement of K + ions along the pore ( coupling ion permeation to pore gating through electro--steric repulsion might be a more 589 general activation mechanism than previously estimated (Hilgemann, 2020). 590…”