Editorial [Hot Topic: Potassium Channels (Guest Editor: Dr. Vincenzo Calderone)]

Editorial Potassium channels are membrane proteins which selectively allow potassium ions to flow across the cell membrane, following the electrochemical gradient. Since the extracellular potassium concentration is greatly lower than the intracellular one, the opening of potassium channels typically determines an outward current of these ions, causing a shift of the resting membrane potential towards the potassium equilibrium potential (hyperpolarisation) or the recovery of the resting potential in a depolarised membrane (repolarisation). Both these mechanisms can counteract the excitatory (depolarising) stimuli, generally due to the inward flows of other important cationic species (calcium and sodium). This fundamental role of potassium channels is inmost involved in almost all the main cell activities, such as the excitability of neurons and muscle cells, the shaping of action potentials, the coupling of many chemical and or mechanical stimuli with given intracellular events, the function of secretive cells, etc., and thus drugs activating potassium channel seem to represent interesting tools for the potential treatment of several pathological conditions. Because of their relaxing effects on smooth muscle cells, they have been investigated as vasodilators and anti-asthmatic agents. Their neuroprotective activity furnished a strong rational basis for the use in neurodegenerative disorders and/or in stroke. Other experimental studies indicated potassium channel activators as useful agents for treatment of epilepsy and pain. More recent evidence, indicating a relevant role of potassium channels expressed on the myocardial mitochondria in the "ischaemic pre-conditioning", suggested an intriguing scenario for potassium channel activators as innovative cardio-protective anti-ischaemic drugs. Although all these therapeutic perspectives have been well supported by a plethora of convincing experimental studies, the availability of potassium channel activators in the clinical practice is still quite limited. There are, at least, two main reasons for this apparent antinomia between the hypothesised potentialities of these drugs and their real application. Potassium channels are sub-divided into a very large number of types and subtypes, but only few of them have been selected for the development of selective drugs. Many drugs presently available show an appreciable selectivity for given potassium channel types, but, generally, these targets are largely expressed in many districts and, hence, this determines the presence of several side-effects accompanying a wished pharmacological activity. Therefore, the individuation of a given potassium channel subtype closely associated with a particular role (and, ideally, in a particular district), as well as the development of appropriate pharmacophore models able to confer to a potassium channel activator a satisfactory selectivity for a given sub-type (or, at least, to confer an adequate tissue-selectivity due to pharmacokinetic properties), seems to represent the most challenging issue for the pharmacologists and medicinal chemists working in the field of potassium channel drugs. In this special issue, William Dalby-Brown and colleagues present an intriguing and detailed review focused on the voltage-operated potassium channel Kv7 type as a recent target of the pharmacological/pharmaceutical investigation. Indeed, some subtypes of this channel play clear and distinct roles in human diseases, offering some promising perspectives for the development of selective modulators (openers as well as blockers). The large-conductance calcium-activated potassium (BK) channel, has been the topic of intense research, in the recent years. A relatively large amount of heterogeneous compounds acts as BK-openers and many of them have been obtained from the structural development of pioneer benzimidazolone derivatives. In his interesting paper, Sheng-Nan Wu and co-workers give an overview on the pharmacological roles of BK channels and on the BK-activating properties of several compounds, which are not structurally related with the benzimidazolone BK-activators and, therefore, can represent a useful and original template for the development of new chemical classes of BK-openers. The ATP-sensitive (KATP) one is surely the most studied, among the different types of potassium channels and about two decades of investigations furnished a wide collection of KATP-activators. Indeed, these channel modulators belong to extremely diversified chemical families and the large number of compounds of each family allowed to trace clear structure-activity relationships..........