K+ channel blockers: novel tools to inhibit T cell activation leading to specific immunosuppression.
During the last two decades since the identification and characterization of T cell potassium channels great advances have been made in the understanding of the role of these channels in T cell functions, especially in antigen-induced activation. Their limited tissue distribution and the recent discovery that different T cell subtypes carrying out distinct immune functions show specific expression levels of these channels have made T cell potassium channels attractive targets for immunomodulatory drugs. Many toxins of various animal species and a structurally diverse array of small molecules inhibiting these channels with varying affinity and selectivity were found and their successful use in immunosuppression in vivo was also demonstrated. Better understanding of the topological differences between potassium channel pores, detailed knowledge of toxin and small-molecule structures and the identification of the binding sites of blocking compounds make it possible to improve the selectivity and affinity of the lead compounds by introducing modifications based on structural information. In this review the basic properties and physiological roles of the voltage-gated Kv1.3 and the Ca2+-activated IKCa1 potassium channels are discussed along with an overview of compounds inhibiting these channels and approaches aiming at producing more efficient modulators of immune functions for the treatment of diseases like sclerosis multiplex and type I diabetes.
Panyi
G
G
Department of Biophysics and Cell Biology, University of Debrecen, Medical and Health Science Center, 98. Nagyerdei krt., Debrecen 4012 Hungary. panyi@jaguar.dote.hu
Possani
L D
LD
Rodríguez de la Vega
R C
RC
Gáspár
R
R
Varga
Z
Z
D000595:Amino Acid Sequence; D000818:Animals; D003064:Cnidarian Venoms / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000494:pharmacology*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating; D051664:Kv1.3 Potassium Channel / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
D003064:Cnidarian Venoms; D007166:Immunosuppressive Agents; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D011720:Pyrazoles; D011804:Quinolines; C095391:ShK neurotoxin; C411671:TRAM 34; C094805:WIN 17317-3