Ion Channels and Relevant Drug Screening Approaches

In this issue of SLAS Discovery, we present a special collection of manuscripts, including three original research papers and one review, that reflect recent advances and continuing challenges in the development and application of assay technologies to drug discovery for ion channel targets. First, though, we provide our perspectives on the specific challenges and opportunities in this field.

Transport proteins, which are embedded in and span most cell membranes, play essential roles in regulating ionic homeostasis in all mammalian cell types. It is well established that the electrolyte compositions of intracellular and extracellular fluids in the human body are very different, with K⁺ (~140 mM) being the dominant cation intracellularly and Na⁺ (~140 mM) and Cl^– (~100 mM) being the dominant ions extracellularly. In fact, most ions have multiple-fold differences in concentration across the plasma membrane and across the membranes of intracellular organelles. Ionic concentration gradients are established and maintained by active, energy-requiring pumps, including the electrogenic Na⁺/K⁺-ATPase in the plasma membrane and SERCA, a Ca²⁺-ATPase that is present in the membrane of the sarcoendoplasmic reticulum. These concentration gradients are possible because lipid-based membranes are impermeable to ions. Ion channels constitute a class of pore-forming proteins that provide regulated permeability pathways that allow the passive flow of ions from one side of the membrane to the other. Ion channels can be grouped into families that are defined by their structural features, tissue localization, and functional and pharmacological characteristics. Typically, they are classified according to their gating mechanism, for example, voltage-gated or ligand-gated and, in some cases, by their permeant ion(s):¹ cation channels are permeable either selectively or nonselectively to K⁺, Na⁺ and Ca²⁺, whereas anion channels are permeable to Cl^–.