Editorial[Hot Topic:Membrane Channels as Therapeutic Targets (Executive Editor: Jean-Claude Herve)]

The production of new molecular entities endowed with salutary medicinal properties is a formidable challenge that involves several steps and requests rational target identification, recognition and avoidance of adverse properties of therapeutics before commitment to clinical trials, monitoring of clinical efficacy using surrogate markers and individualized approaches to disease treatment. The first to face up to is the initial identification and selection of macromolecular targets upon which de novo drug discovery programs can be initiated. A drug target needs to answer several criteria (as known biological function(s), robust assay systems for in vitro characterisation and high-throughput screening) and to be specifically modified by and accessible to small molecular weight compounds in vivo. Membrane channels have many of these attributes and can be viewed as suitable targets for small molecule drugs. Channels are membrane-embedded proteins that contain one or several integral pore(s) able to open and to close (a process called gating), allowing ions and sometimes small molecules to flow across the cell membrane in a regulated manner. Their gating can be modulated by various stimuli including changes in membrane voltage, binding of extracellular or intracellular ligands, membrane stretch, enzymes and Gproteins. They play critical roles in a broad range of physiological processes, including electrical signal transduction, chemical signalling (involving different second messengers), transepithelial transport, regulation of cytoplasmic or vesicular ion concentration and pH, as well as regulation of cell volume. Channel dysfunction may lead to a number of diseases termed channelopathies, and a number of common diseases (e.g. epilepsy, hypertension, arrhythmia, chronic pain or type II diabetes) are primarily treated by drugs that modulate ion channel activities. The cell-based methods for evaluating membrane channel pharmacology are based on several distinct techniques such as electrophysiology, fluorescence, radioligand binding or displacement, and radiotracer flux assays. A better understanding of membrane channel structures and of channel functions has been achieved in recent years by three main scientific advances, the patch-clamp technique, the use of selective neurotoxins and the cloning and sequencing of genes. They allowed investigating the pharmacological effects of traditional (antiarrhythmic, antiepileptic, ...) drugs and the development of new approaches. This issue of Current Pharmaceutical Design, the last of four parts, for which I have the honour to be Executive Guest Editor, addresses topical issues to some of these channels. The properties of ionic channels are most often investigated by means of voltage clamp approaches, particularly the patch clamp technique, which allows direct electrical measurement of ion channel currents while simultaneously controlling the cell’s membrane potential. It relies on the use of a fine tipped glass capillary to make contact with a patch of a cell membrane in order to form a giga-ohm seal. However, these assays are technically challenging and notoriously low-throughput. The recent development of several automated electrophysiology platforms has greatly increased the throughput of whole cell electrophysiological recordings, allowing them to play a more central role in ion channel drug discovery. Birgit Priest, Andrew Swensen and Owen McManus [1] present these technologies, which promise to enable more rapid and efficient identification of specific ion channel modulators, which will, in turn, aid efforts to understand the functional roles of specific ion channels and provide new therapeutic approaches to disease states. Pacemaking is an electrical phenomenon, based on the function of ion channel proteins expressed on the membrane of some types of specialized cells (either cardiomyocytes, neurons, or smooth muscle cells), which allows them to generate repetitive action potentials at a constantly controlled rate. The properties of “pacemaker” currents (termed Ih (h for hyperpolarization-activated), If (f for funny) or Iq (q for queer)) are deemed unique, particularly its direct regulation by intracellular cyclic nucleotides............