Ion homeostasis, channels, and transporters: an update on cellular mechanisms

Abstract

The steady-state maintenance of highly asymmetric concentrations of the major inorganic cations and anions is a major function of both plasma membranes and the membranes of intracellular organelles. Homeostatic regulation of these ionic gradients is critical for most functions. Due to their charge, the movements of ions across biological membranes necessarily involves facilitation by intrinsic membrane transport proteins. The functional characterization and categorization of membrane transport proteins was a major focus of cell physiological research from the 1950s through the 1980s. On the basis of these functional analyses, ion transport proteins were broadly divided into two classes: channels and carrier-type transporters (which include exchangers, cotransporters, and ATP-driven ion pumps). Beginning in the mid-1980s, these functional analyses of ion transport and homeostasis were complemented by the cloning of genes encoding many ion channels and transporter proteins. Comparison of the predicted primary amino acid sequences and structures of functionally similar ion transport proteins facilitated their grouping within families and superfamilies of structurally related membrane proteins. Postgenomics research in ion transport biology increasingly involves two powerful approaches. One involves elucidation of the molecular structures, at the atomic level in some cases, of model ion transport proteins. The second uses the tools of cell biology to explore the cell-specific function or subcellular localization of ion transport proteins. This review will describe how these approaches have provided new, and sometimes surprising, insights regarding four major questions in current ion transporter research. 1) What are the fundamental differences between ion channels and ion transporters? 2) How does the interaction of an ion transport protein with so-called adapter proteins affect its subcellular localization or regulation by various intracellular signal transduction pathways? 3) How does the specific lipid composition of the local membrane microenvironment modulate the function of an ion transport protein? 4) How can the basic functional properties of a ubiquitously expressed ion transport protein vary depending on the cell type in which it is expressed?

ATP and PIP2 dependence of the magnesium-inhibited, TRPM7-like cation channel in cardiac myocytes

“…ATP acts as substrate for lipid kinases that phosphorylate phosphatidylinositol (PI) to higher-order phosphoinositides. Among these phosphoinositides, PIP 2 modulates many ion channels (7,16,43). Its precursor, phosphatidylinositol 4-phosphate, is synthesized from PI by a reaction catalyzed by phosphatidylinositol 4-kinase (PI4-kinase) that can be inhibited by wortmannin at high concentrations (IC 50 Ն 50 -140 nM; Refs.…”

“…Thus MIC channels in cardiac myocytes belong to the group of channels modulated by PIP 2 . Local PIP 2 is proposed to regulate ion channels by electrostatic modulation, either directly by binding to intracellular components of the channel or indirectly by altering interactions between channel and other regulatory units (7,16). More work is still required to understand the mechanisms by which PIP 2 modulates cardiac MIC channels.…”

EphB2 and ephrin-B2 regulate the ionic homeostasis of vestibular endolymph

“…The ability to transport ions and water across cellular membranes is critical for a diverse array of basic processes such as in the regulation of pH, ionic homeostasis, and volume of extracellular Xuids (Jentsch et al, 2004(Jentsch et al, , 2005. Although the transporters and channels that facilitate ion and water transport across cell membranes are well known (Dubyak, 2004;Kass, 2005), the molecular mechanisms and signal transduction events that regulate transport/channel activities remain poorly understood. Our data brings forth the novel idea that EphB2:ephrin-B2 bidirectional signaling regulates the ionic homeostasis of vestibular endolymph.…”

Fatty Acid-Fuelled Transmembrane Chloride Transport

“…[1] Lipid bilayer membranes of cells and intracellular organelles facilitate the storage of biochemical energy by maintaining ion homeostasis and electrochemical gradients. [2] For instance, the typical extracellular chloride concentration (~120 mM) is much higher than the cytosolic chloride concentration (5-40 mM). [3] All cellular ion (e.g.…”