Grand Challenge for Ion Channels: an Underexploited Resource for Therapeutics

channelopathies were known, but most of these drugs were used empirically and were found to act on ion channels afterward. Now our knowledge about their role in diseases have validated ion channels as very promising druggable targets. What are the difficulties encountered in ion channel drug discovery? A major problem of ion channel drugs regards the side effects. An ion channel type is often expressed in many cell types, and it is important to target the ill tissue without altering the normal function of the others. Let’s take the example of voltage-gated sodium channels, which are expressed in many excitable tissues including the heart and the central nervous system. The use of sodium channel blockers to counteract hyper-excitability in peripheral tissues, such as the skeletal muscle in myotonia or the nociceptive neuron in neuropathic pain, can be significantly limited by the side action on cardiac or CNS sodium channels. Thus the International Association for the Study of Pain recommends orally available sodium channel blockers as third-line treatment in neuropathic pain, mainly because of their potential side effects (Dworkin et al., 2007). Up to now, to limit these unwanted effects, a peculiarity of sodium channel blockers was exploited, that is the use-dependence – the higher the frequency of action potential firing, the greater is the block of sodium channels – allowing a rather specific action of drugs in hyperexcited cells. A more recent successful therapy based on a channel gating-dependent mechanism of action is that of ranolazine in angina pectoris, which appears to inhibit quite specifically the guilty late sodium current that is increased in the ischemic myocyte (Chaitman, 2006). An other manner to limit the side effects is to restrain body exposure when it is possible, such as with topical lidocaine for post-herpetic pain or intrathecal ziconotide for severe chronic pain. On an other hand, the search for drugs specific to channel subtypes has Grand challenge for ion channels: an underexploited resource for therapeutics