Channels and channelopathies

Ion channels form pores to gate ion flux across cell membranes, enabling cells to generate resting membrane potentials and action potentials and to regulate cell volume, for example. Tiny, yet intricately complex integral membrane proteins form ion channels that are present in an impressive multitude of classes and structures. Classified by their gatekeeper mechanisms, voltage-controlled (Salunkhe et al. 2015) (Zhang et al. 2014) and ligand-controlled (Barragan et al. 2015) channels may be distinguished from the channels controlled by biochemical modification through, for example, phosphorylation (Lang et al. 2015). Other examples include mechanosensitive channels of the transient receptor potential families (Pedersen et al. 2015). The discovery and description of ion channel structure and function has led to more than one Nobel Prize. In 1952, British biophysicists Alan Hodgkin and Andrew Huxley published their Nobel Prize-winning research results on the conductive properties of cell membranes and the action potential, in which some basic properties of the ion channels involved in action potential generation were first characterized (Hodgkin & Huxley 1952). Kenneth S. Cole and Richard F. Baker had already in the early 1940s paved the ground for this breakthrough (Cole & Baker 1941). However, it took another 30 years until Bernard Katz and Ricardo Miledi via noise analysis successfully verified the substrate which his predecessors had postulated (Katz & Miledi 1973), before in 1991 the Nobel Prize in Physiology or Medicine was awarded jointly to Erwin Neher and Bert Sakmann for their discoveries concerning the function of single ion channels in cells (Nobelprize.org), in recognition of their invention of the patch clamp technique. They were not the last ones, though. The Nobel Prize in Chemistry 2003 was awarded ‘for discoveries concerning channels in cell membranes’ jointly with one half to Peter Agre ‘for the discovery of water channels’ and with one half to Roderick MacKinnon ‘for structural and mechanistic studies of ion channels’ (ibid). Channelopathies are one extreme example of a disease entity, which may be very tragic for the individual patient, while, on the other hand, the function of many ion channels could only have been learned from mutations that occurred either in patients or in animals in the context of experimental set ups (Jentsch et al. 2004). Channelopathies or ion channel diseases result from dysfunctional ion channel subunits or dysfunctional proteins that regulate ion channels. Channelopathies are often present at birth. Some ion channel diseases are extremely rare, with only single cases published, while others are among the most frequent inherited conditions, such as cystic fibrosis (CF), which affects about one in every 2500 newborns of Northern European/Caucasian ancestry (Song et al. 2014) (Jentsch et al. 2004). Acquired ion channel dysfunctions may, e.g., be caused by autoimmune reactions, ischaemia–reperfusion injury (Johansson et al. 2015) or side effects of pharmaceutical agents (Kishore et al. 2015). Novel insights into channel physiology and pathophysiology keep coming. As soon as a review paper or textbook publishes a comprehensive overview of the ion channels associated with certain human pathologies, new ones have been described in the meantime. Seven general classes of ion channelopathies have been described to affect (i) cation channels, (ii) sodium channels, (iii) potassium channels, (iv) calcium channels, (v) chloride channels, (vi) water channels and (vii) gap junction proteins (Jentsch et al. 2004). Renal channelopathies may affect all segments of the nephron, which displays the specialized arrays of channels for the subsequent processing of water, ions, amino acids and other substances following primary urine formation. The gain-of-function mutation in ENaC leading to Liddle's syndrome is well understood (Jentsch et al. 2004), while other dysfunctions may secondarily affect ENaC. Purinergic signalling controls renal function through channel activity modification, as, for example, signalling via P2Y2 controls aldosterone-dependent ENaC activity on the principle cells reabsorbing sodium (Persson & Carlström 2015) (Mironova et al. 2015), with important roles in the pathophysiology of hypertension, which remain to be elucidated in full detail (Menzies et al. 2015) (Franco et al. 2015). The negative effects of a diet high in NaCl in patients with proteinuric kidney disease had been known for a long time; purinergic signalling seems to provide a missing link (Svenningsen et al. 2014). Recently, it was demonstrated how proteinuric kidney disease contributes to an increased blood pressure, which itself accelerates the progression of kidney disease, when proteolytic enzymes leaking across the glomerular barrier activate ENaC and thus sodium reabsorption in the distal nephron (Palm 2015). Renal blood flow is intricately regulated through an array of ion channels, with Kv7 having recently been added (Salomonsson et al. 2015). Therapeutic options for channelopathies have often been limited to symptomatic patient management. Cystic fibrosis (CF) patients, for example, receive pharmacological therapies and small compound correctors to control malnutrition, intestinal and airway obstructions and chronic bacterial infections. Although, mind, symptomatic therapy must not be confused with palliative care: think of the lives saved by implantable cardioverter defibrillators in survivors of sudden cardiac death and their affected, yet still asymptomatic relatives with long QT syndromes (Sedmera et al. 2015). Due to the relatively high prevalence and the severe prognosis of the children affected by CF, and recent breakthroughs in gene transfer technology, the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) channelopathy has been studied extensively. First promising results point towards a sustainable gene therapy using wild-type copies of the CFTR gene transferred to the lung, with recent success in a clinical trial (Alton et al. 2015). Channelopathies are not necessarily fatal inherited syndromes; other examples include lithium-induced diabetes insipidus or uterine insufficiency (Wray et al. 2015). The SLC26A3 anion transporter in the apical membrane of colonic mucosa absorbs Cl− from the gut in exchange for HCO3−, maintaining together with an Na+/H+ exchange most of the colonic NaCl absorption. SLC26A3 mutations lead to autosomal recessive congenital chloride diarrhoea (CLD), in which strong EnaC upregulation cannot compensate for the net NaCl and fluid loss, interestingly associated with an increased risk of inflammatory bowel disease due to a disruption in the mucosal barrier, as recently reported (Ishiguro 2014); (Xiao et al. 2014). Genetic diagnosis of channelopathies has become popular. Online, one may already today order a commercialized ‘transfer of code to diagnosis’ (see, e.g., Cegat.de). Close links between biochemical research and patient care must be maintained, not only to avoid both unnecessary delays in therapeutic approaches reaching the patient, but also to protect the patients from unfiltered test results lacking the medical background to interpret their consequences for individuals and their families. None.