The Ca2+-activated K+ channel of intermediate conductance:a possible target for immune suppression.
The intermediate conductance Ca2+-activated K+ (IK) channel is distinguished from the functionally related Ca2+-activated K+ channels of smaller and larger unitary conductance by its molecular structure, pharmacology, tissue distribution and physiology. Like many K+ channels, IK is an assembly of four identical subunits each spanning the membrane six times and each contributing equally to the K+ selectivity pore positioned centrally in the complex. The IK channel gains its high sensitivity to intracellular Ca2+ from tightly bound calmodulin, and its activity is independent of the membrane potential. Several toxins including charybdotoxin and the more selective mutant, Glu32-charybdotoxin, maurotoxin and stichodactyla toxin potently block IK channels. Among blockers of the IK channel are also several small organic molecules including the antimycotic clotrimazole and the close analogues TRAM-34 and ICA-17043, as well as the antihypertensive, nitrendipine. The IK channel is distributed in peripheral tissues, including secretory epithelia and blood cells, but it appears absent from neuronal and muscle tissue. An important physiological role of the IK channel is to help maintain large electrical gradients for the sustained transport of ions such as Ca2+ influx that controls T lymphocyte (T cell) proliferation. In this review, special attention is given to an analysis of the use of IK blockers as potential immunosuppressants for the treatment of autoimmune disorders such as rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis.
Jensen
B S
BS
Section of Ion Channel Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, DK-2750 Ballerup, Denmark. bsj@neurosearch.dk
Hertz
M
M
Christophersen
P
P
Madsen
L S
LS
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D015640:Ion Channel Gating / Q000187:drug effects; D017136:Ion Transport / Q000187:drug effects; D051664:Kv1.3 Potassium Channel; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D018448:Models, Immunological; D008958:Models, Molecular; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000188:drug therapy; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000502:physiology; D011487:Protein Conformation; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology
D002121:Calcium Channel Blockers; D007166:Immunosuppressive Agents; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496973:KCNA3 protein, human; C496923:KCNN4 protein, human; C496974:Kcna3 protein, mouse; C496975:Kcna3 protein, rat; C496925:Kcnn4 protein, mouse; D051664:Kv1.3 Potassium Channel; D010455:Peptides; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D014688:Venoms; D011188:Potassium; D002118:Calcium