Potassium Channels as a Target for Clinical Therapeutics

Despite the great progression of interventional cardiology, Ischaemic heart disease (IHD) remains one of the most common causes of morbidity and mortality worldwide. In this context, pharmacological cardioprotection seems to be another important strategy in the treatment of IHD. The landmark discovery of ischaemic preconditioning by Murray et al., the phenomenon that prior exposure to multiple brief periods of ischaemia may confer protection against a subsequent sustained ischaemic insult, was followed by studies to elucidate the cellular mechanism underlying this phenomenon of innate cardioprotection. The pathophysiological relevance of ATP-sensitive K⁺ channels (K^ATP ) to ischaemic heart disease and cardioprotection has been marked by numerous observations. In this chapter the role of sarcolemmal and mitochondrial K^ATP channels in the mechanism of ischaemia preconditioning, and its applications, potential and real, for patients suffering from ischaemic heart disease will be discussed.

Although, most of the persistent and life-threatening arrhythmias can be treated with surgical and interventional cardiologic methods, pharmacological intervention is still the most common and accessible way of treatment. Recently, antiarrhythmics are very often combined with electrotherapy and ablation in so-called hybrid therapy. Among different antiarrhythmic drugs, potassium channel blockers deserve special attention. All of the compounds able to block repolarizing potassium channels can be divided in to two groups: IIIa which prolong action potential duration (APD) at fast heart rates (amiodarone, dronedarone, dofetilide) and group IIIb that prolonging APD at slow heart rates ( bretylium, sotalol). Therefore, in this chapter, the clinical efficacy and the most important clinical trials of above mentioned drugs will be discussed in such arrhythmias as atrial, ventricular tachycardia, atrial flutter, atrial fibrillation and cardiac sudden death.

There is one specific type of K⁺ channels profoundly involved in regulation of release of hormone insulin and inextricably connected to pathogenesis of diabetes mellitus. It is ATP-sensitive K⁺ channel (K_ATP). Recently, along with advances in genetic testing, a growing number of permanent neonatal diabetes (PND) has been diagnosed, which is a monogenic form of diabetes of even earlier onset than maturity onset diabetes of the young (MODY). Neonatal diabetes can result from mutations in Kir6.2 or sulfonylurea receptor (SUR1) subunits of the ATP-sensitive K⁺ channel. The pathogenesis is based on the mechanism of permanent activation and wide opening of the K_ATP potassium channel of the β-cells. An important and interesting feature of the disease clinical picture is sustained therapeutic response to sulfonylureas in the treatment of neonatal diabetes caused by mutation in the KCNJ11 and ABCC8 genes. Mechanism of action of this class of medicines involves interaction with the SUR1 subunit of the K_ATP channel in the β cell. However, there are some types of neonatal diabetes which fail to respond to the sulfonylurea therapy. An example of this is the most severe phenotype of neonatal diabetes accompanied with disorders of the nervous system, muscle weakness and psychomotor development delay, which is a so-called DEND syndrome. Analogs of GLP-1 and antagonist of GLP-1 receptor may provide a new way of treatment in K_ATP dependent disorders. These hormones may modulate the beta cells response by influencing K_ATP channels and cAMP independently.

Apart from heart and pancreatic islets, potassium channels are widely distributed in the smooth muscle and nerves. Several different types of K⁺ channels located in the above mentioned tissues have a crucial role in the regulation of many functions. Their modulation is seriously considered in the treatment of diseases such as hypertension, bronchial asthma, epilepsy, different kinds of pain, and stroke. These are some of the most common and serious neurological defects that appear usually as a consequence of untreated hypertension, and without satisfactorily up to date pharmacological treatment. This chapter will discuss the substances related to the different kinds of potassium channels which are currently in clinical trials or are already clinically used for treatment of above mentioned diseases.

This chapter focuses on molecular changes in subunits of potassium channels, which are relevant to various disorders. Numerous studies on the diversity of amino acid sequences of potassium channels have been conducted. Since over 50 mammalian genes encode the chief subunits of potassium channels, it is difficult to carry out the research. Each of these genes can undergo a lot of multiple mutations which significantly influence potassium channel function. If we take into consideration all the changes, the functional diversity of the channels extends radically. In addition, these genes undergo RNA processing, such as alternative splicing, which leads to multiplication of protein products for each gene. As a result, the number of different mammalian principal subunits increases to over a few hundred. Considering other changes arising in the processes of gene transcription, RNA processing, post-translational modification and protein degradation, the total number of different functional potassium channel subtypes is probably much higher.

In the first part of this chapter we would like to present the diversity of mutations in genes coding for potassium channels as well as their influence related to the most important defects, diseases and functional impairments (from the clinical point of view). We will rather focus on novel information in this field, published during the last few years. In the following sections, we will describe other modifications that influence potassium channels, such as alternative splicing, RNA editing and posttranslational modifications.