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

A significant difficulty the pharmaceutical industry has 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. Membrane channels are macromolecular protein complexes embedded in the lipid bilayer and containing aqueous central pores allowing the passage of ions and sometimes of small molecules. Their functions are finely tuned by a variety of modulators, such as enzymes and G-proteins. 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, arrhythmia or type II diabetes) are primarily treated by drugs that modulate ion channel activities. 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 to investigate the pharmacological effects of traditional (antiarrhythmic, antiepileptic, ...) drugs and the development of new approaches. This issue of Current Pharmaceutical Design, the second of three parts, for which I have the honour to be Executive Guest Editor, addresses topical issues to some of these channels. Despite their disease relevance, ion channels remain until now largely under exploited as drug targets. The ability to apply large-scale screening formats to measures of ion channel function offers immense opportunities for drug discovery and academic research. Several technologies now allow to screen large numbers of compounds and natural products on ion channel functions to find novel drugs. Application of these technologies has vastly improved the capabilities of ion channel drug discovery and provides an avenue to accelerate discoveries of ion channel biology. Mark Treherne describes [1] ion channel screening platforms now available, together with some of their inherent advantages and limitations. Neuronal acetylcholine ion channel receptors (nAChRs), that exist in several subtypes resulting from a different organisation of various subunits around the central ion channel, are involved in a variety of functions and disorders of the central nervous system. Cecilia Gotti et al. [2] discuss the molecular basis of brain nAChR structural and functional diversity mainly in pharmacological and biochemical terms, and summarise current knowledge concerning the newly discovered drugs used to classify the numerous receptor subtypes and to treat the brain diseases in which nAChRs are involved. Voltage-gated sodium channels mediate regenerative inward currents that are responsible for the initial depolarisation of action potentials in excitable cells. Advances in molecular biology have led to important new insights into the molecular structure of the sodium channel and have shed light on the relationship between channel structure and channel function. Kaoru Yamaoka et al. [3] present an overview of the various toxins and drug molecules affecting the gating behaviour of sodium channels, providing important clues on the nature of mobile structures involved in channel gating. Voltage-gated L-type Ca2+ channels control depolarisation-induced Ca2+ entry in different electrically excitable cells, including mammalian heart but play also crucial roles in other processes, as insulin secretory response, severe pain or ischemic stroke. David Triggle [4] discusses the mechanisms of action of L-type Ca2+ channels blockers as well as the limitations on their use (e.g. their little selectivity between subtypes of the L-type channels). Potassium channels are a diverse and ubiquitous family of membrane proteins present in both excitable and non-excitable cells. Members of this channel family play critical roles in cellular signalling processes regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, cell volume regulation, auditory function, hormone secretion, immune function, cell proliferation, etc. Specific modulators have been identified for a limited number of K+ channel subtypes. Kim Lawson and Neil McKay [5] overview the current knowledge available concerning K+ channels as therapeutic targets. More than 1300 different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis, a disease characterised by deficient epithelial Cl- secretion and enhanced Na+ absorption. Frédéric Becq [6] summarises the recent evolution of CFTR pharmacology and particularly how high throughput screening assays have been developed to identify novel molecules, some of them probably constituting a reservoir of future therapeutic agents for cystic fibrosis. Type-2 diabetes mellitus is considered to be due to the failure of glucose metabolism to stimulate pancreatic b-cell electrical activity, calcium influx, and insulin secretion via regulation of the open probability of the ATP-sensitive K (KATP) channels.....