ABSTRACT
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.
Subject(s)
Immunosuppressive Agents/pharmacology , Lymphocyte Activation , Potassium Channel Blockers/pharmacology , T-Lymphocytes/drug effects , Amino Acid Sequence , Animals , Cnidarian Venoms/chemistry , Cnidarian Venoms/pharmacology , Drug Design , Humans , Immunosuppressive Agents/chemistry , Intermediate-Conductance Calcium-Activated Potassium Channels/chemistry , Intermediate-Conductance Calcium-Activated Potassium Channels/drug effects , Intermediate-Conductance Calcium-Activated Potassium Channels/metabolism , Ion Channel Gating , Kv1.3 Potassium Channel/chemistry , Kv1.3 Potassium Channel/drug effects , Kv1.3 Potassium Channel/metabolism , Models, Molecular , Molecular Sequence Data , Molecular Structure , Potassium Channel Blockers/chemistry , Protein Conformation , Pyrazoles/chemistry , Pyrazoles/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Structure-Activity Relationship , T-Lymphocytes/immunology , T-Lymphocytes/metabolismABSTRACT
Antimicrobial peptides (AMPs) are essential components of host defences against infectious microrganisms. In chelicerate organisms they have been implicated in three alternative defensive systems: one is defined by the immediate up-regulation of genes encoding AMPs, another is characterized by the inducible systemic release of AMPs from cellular reservoirs and the third alternative is the systemic constitutive production of AMPs. In this work we used a differential high-performance liquid chromatography and mass spectrometry approach to show that septic injury elicits an immune response in the haemolymph of the Mexican scorpion Centruroides limpidus limpidus. We isolated several haemolymph components, one of which was characterized extensively (amino acid sequence, disulphide pairing, cDNA and genomic clones) and demonstrated to be a novel member of the invertebrate defensin family and consequently named C. limpidus limpidus defensin-like peptide (Cll-dlp). This peptide accumulates in the haemolymph in response to septic injury, independently of transcriptional regulation.
