Ion channels

New explanations for old diseases

Ion channels are protein pores in the cell membrane that allow the passage of ions down their respective electrochemical gradients.1 The ubiquitous presence of ion channels among cells of unicellular and multicellular organisms suggests their importance in maintaining cellular integrity. Our understanding of the part that they play in disease has grown rapidly in the past few years, as a result of being able to explore the functional properties of ion channels in living cells.

Ion channels are classified broadly by the principal ion they carry (sodium, potassium, calcium, chloride) and the mechanisms by which they are opened and closed. Acetylcholine, for example, is a receptor specific agonist that acts at the postsynaptic membrane of the motor end plate to open chloride channels. Changes in membrane voltage or to concentrations of intracellular ions and molecules such as calcium and ATP can also open ion channels. The normal but unequal distribution of ions across the cell membrane can lead to the generation of a membrane potential as great as 100 mV.

Hodgkin and Huxley were the first to study ion channels, in 1952. They examined the squid giant axon using the voltage clamp technique.2 They focused principally on the ionic mechanisms facilitating communication of information within or between nerve or muscle cells, which led to current knowledge of the action of voltage gated ion channels. Not until Neher and Sakmann developed the patch clamp technique (for which they received the Nobel prize in 1991), however, did it became feasible to study other types of cell and resolve currents passing through single channels.3 Their work means that conformational changes of biological molecules in situ and in real time can be described, as well as conformational changes in small cells such as lymphocytes or epithelial cells. More important, however, are the changes in the functional properties of ion channels that may be associated with disease processes.

Abnormalities of ion channels were initially believed to be confined to excitable cells. Hyperkalaemic periodic paralysis, for example, arises from a defective voltage activated sodium channel in skeletal muscle.4 More recently, abnormalities of a calcium dependent potassium channel have been found in cavernous smooth muscle from some men with erectile dysfunction.5 A complicated regulatory relation exists in cavernous smooth muscle cells between membrane potential, the activity of calcium dependent potassium channels, and voltage activated calcium channels. These voltage activated calcium channels in turn modulate intracellular calcium ion concentration, which is important in the smooth muscle relaxation that precedes an erection. The impaired hyperpolarising ability of corporal smooth muscle arising from defective calcium dependent potassium channels may account for the failure of smooth muscle to relax. This results in impotence.

Even in tissues traditionally not considered to be excitable, however, dysfunction of ion channels has been shown to cause disease. Well known examples include cystic fibrosis and diabetes mellitus. Cystic fibrosis arises from a failure of chloride ions to pass through the so called cystic fibrosis transmembrane regulator protein. In normal cells cyclic AMP activates cyclic AMP dependent protein kinase A, in turn stimulating cyclic AMP dependent transepithelial transport of chloride ions. In cells from patients with cystic fibrosis the cystic fibrosis transmembrane regulator fails to respond to protein kinase A stimulation, resulting in increased intracellular chloride ion concentration.6 This kind of new knowledge has been applied to devise new therapeutic strategies. In the case of cystic fibrosis, attempts at correcting the abnormal transmembrane regulator have been made by gene therapy, with early favourable reports.7

Glucose metabolism is linked to pancreatic cell insulin secretion through a sequence of events entailing changes in the ratio of ATP to ADP concentration, closure of ATP sensitive potassium channels, membrane depolarisation, and the opening of voltage sensitive calcium channels. The rapid influx of calcium results in release of stored granules containing insulin. Defects in this mechanism are thought to contribute to the development of diabetes mellitus.8 Sulphonylureas, discovered by serendipity many years ago to be effective in treating diabetes mellitus, block ATP sensitive potassium channels.

Recently, evidence has begun to emerge of other roles for ion channels such as in the development of cancer, tumour invasion, and possibly metastasis. Voltage gated sodium channels that are similar to those in excitable tissues are present in small cell lung cancer cell lines9; they are also associated with invasion by rat10 and human11 prostate cancer cells in vitro. Chloride channels have been identified in primary cultures of cervical epithelium from patients with cervical cancer but not in cultures from patients who do not have cervical cancer.12 13The functional role of these chloride channels in cervical carcinogenesis remains to be determined.

As ion channel subtypes and membrane potential have been implicated in many aspects of cell biology, including the cell cycle, apoptosis, cell adhesion, cell motility, exocytosis, and multidrug resistance, all of which are relevant to the neoplastic process, reports such as these are not surprising.1415The multiple roles of ion channels in normal and altered physiology explain some current pharmacological mechanisms and point to potentially promising new interventions and therapeutic strategies. These include antisense oligonucleotide technology or gene therapy to introduce or restructure ion channels and modify cellular action potentials, ion transport, or the membrane potential profile.7 Evidence for the role of ion channels in disease continues to grow, and treatments given on the basis of ion channel dysfunction could eventually constitute the basis for an entire new class of interventions to treat disease.