Tools of our trade

The compartmentalization of living cells and the generation of chemical and electrical gradients are a prerequisite for life as we know it. A multitude of physiological processes critically depends on ion gradients and selective, regulated permeabilities, which in turn are based on the controlled flow of small inorganic ions over lipophilic membranes. Therefore, ion channels, exchangers and pumps have become to be considered tools of the trade of the physiologist per se. Ion channels are proteins within the cell membrane, which selectively let ions pass, their major features being ion selectivity and gated opening in response to either ligand binding or changes in voltage across the membrane (Jiang et al. 2002a). The latter have been compared to transistors, in which electron flow is controlled by the voltage at the gate electrode (Sigworth 2003). Long before Erwin Neher and Bert Sakmann published their work that led to the discovery of patch clamping in 1976, and for which they were awarded the Nobel Prize in Physiology or Medicine 15 years later (Neher & Sakmann 1976), physiologists had developed refined assumptions about the critical role of ion channels in electrochemical gradient formation, which could then finally be proven to be correct. Although the existence of (protein) structures that let charged particles pass in a controlled manner had been assumed beforehand, Alan Hodgkin and Andrew Huxley, of Cambridge University, succeeded in 1952 in showing the transient and rapid changes in Na permeability that precede and start action potentials along nerve cell membranes (Hodgkin & Huxley 1952). Three years later, Alan Hodgkin, together with Richard Keynes, published the results about the singlefile movement of radioactively labelled K across nerve cell membranes (Hodgkin & Keynes 1955). Notably, the Nobel Prize in Physiology or Medicine 1963 was awarded to John Eccles, Alan Hodgkin and Andrew Huxley for their discoveries on ionic membrane currents. Their work was groundbreaking at its time and followed in quick succession by the characterization of different selective ion channels on cell membranes and the differences in regulatory behaviour between voltageand ligand-gated channels – without ever being able to visualize these structures. It took almost half a century longer until Rod McKinnon, on New Year’s Eve 1997, was able to, by an adapted method related to X-ray crystallography, depict the potassium ions queing up within their channel just as Huxley had predicted (Doyle et al. 1998, Abbott 2002). Given that many breakthroughs in ion channel science have been made relatively recently, it is not surprising that new results are constantly being published, and ion channel-related search terms yield thousands of hits in the current biomedical literature databases. We have selected a few interesting ones from recent issues of Acta Physiologica (Oxford). In 2002, the crystallography-based characterization of calcium-gated potassium channels provided important insights into the mechanism behind gating, and led to the development of an intriguingly simple model of subunit rearrangement that lets a channel move from closed to open state (Jiang et al. 2002a,b, Schumacher & Adelman 2002). Calcium-gated potassium channels have since then been at the focus of very different disciplines: Their modulation may provide novel therapeutic options for preterm labour (Rosenbaum et al. 2012a,b), the development of endothelium-specific antihypertensive agents (Hasenau et al. 2011) and they have recently been shown to be expressed by bone-marrow derived endothelial progenitors of the monocytic lineage (Xu et al. 2012). Cardiac pathophysiology is often closely related to abberations in ion channel expression and function. Recent interesting results have been published on sodium (Jespersen 2011, Duehmke et al. 2012) and potassium channel function (Johansen et al. 2011, Ferrer et al. 2012), with important implications for cardiac action potential conduction and energy metabolism. Renal vasodilation mediated by K(ir) channels interestingly differs in normoand hypertensive animal models (Magnusson et al. 2011). The twoor tandem-pore-domain K+ channels are a special family of ‘leaking channels’, gated by various mechanisms including oxygen, pH, mechanical stretch and G-protein-related 2nd messenger cascades. Traditionally involved in cardiac and CNS-related pathologies, TREK-1 and TREK-2 tandem-pore-domain K+ channels may be involved in post-ischaemic neuroprotection (Kim et al. 2011), while the TASK-3 subgroup is relevant for cellular migration and may hold potential for the development of anticancer strategies targeted at cell mobility (Lee et al. 2012). Calcium channels, many of which are voltage gated, assume important functions in contractile tissues, the