Abstract
BackgroundAlthough the basic scorpion K+ channel toxins (KTxs) are well-known pharmacological tools and potential drug candidates, characterization the acidic KTxs still has the great significance for their potential selectivity towards different K+ channel subtypes. Unfortunately, research on the acidic KTxs has been ignored for several years and progressed slowly.Principal FindingsHere, we describe the identification of nine new acidic KTxs by cDNA cloning and bioinformatic analyses. Seven of these toxins belong to three new α-KTx subfamilies (α-KTx28, α-KTx29, and α-KTx30), and two are new members of the known κ-KTx2 subfamily. ImKTx104 containing three disulfide bridges, the first member of the α-KTx28 subfamily, has a low sequence homology with other known KTxs, and its NMR structure suggests ImKTx104 adopts a modified cystine-stabilized α-helix-loop-β-sheet (CS-α/β) fold motif that has no apparent α-helixs and β-sheets, but still stabilized by three disulfide bridges. These newly described acidic KTxs exhibit differential pharmacological effects on potassium channels. Acidic scorpion toxin ImKTx104 was the first peptide inhibitor found to affect KCNQ1 channel, which is insensitive to the basic KTxs and is strongly associated with human cardiac abnormalities. ImKTx104 selectively inhibited KCNQ1 channel with a Kd of 11.69 µM, but was less effective against the basic KTxs-sensitive potassium channels. In addition to the ImKTx104 toxin, HeTx204 peptide, containing a cystine-stabilized α-helix-loop-helix (CS-α/α) fold scaffold motif, blocked both Kv1.3 and KCNQ1 channels. StKTx23 toxin, with a cystine-stabilized α-helix-loop-β-sheet (CS-α/β) fold motif, could inhibit Kv1.3 channel, but not the KCNQ1 channel.Conclusions/SignificanceThese findings characterize the structural and functional diversity of acidic KTxs, and could accelerate the development and clinical use of acidic KTxs as pharmacological tools and potential drugs.
Highlights
Potassium channels include a large family of membrane proteins that are important in numerous cellular functions including maintenance of resting membrane potential, control of cardiac and neuronal excitability, release of neurotransmitters, muscle contractility, and hormone secretion [1,2,3]
Structure and function studies have further demonstrated that these basic K+ channel toxins (KTxs) modulate Kv1.x channels [5,15], Kv11.1 channels [16,17], large-conductance Ca2+-activated K+ channels (BKCa) [18], intermediate-conductance Ca2+-activated K+ channels (IKCa) [19,20], and small conductance Ca2+-activated K+ channels (SKCa) [21,22]
Molecular diversity of acidic KTxs In this work, we describe the isolation and identification of novel acidic KTxs, and identify nine new transcripts encoding precursors of acidic KTxs from the cDNA libraries of Lychas mucronatus, Isometrus, maculates, Scorpiops tibetanus, Scorpiops jendeki, and Heterometrus spinifer venom glands
Summary
Potassium channels include a large family of membrane proteins that are important in numerous cellular functions including maintenance of resting membrane potential, control of cardiac and neuronal excitability, release of neurotransmitters, muscle contractility, and hormone secretion [1,2,3]. In the last 30 years, these toxins have been used to probe the structural and functional relationships of potassium channels and to develop channelselective pharmacological tools and drug candidates [5,6,7]. Structure and function studies have further demonstrated that these basic KTxs modulate Kv1.x channels [5,15], Kv11.1 channels [16,17], large-conductance Ca2+-activated K+ channels (BKCa) [18], intermediate-conductance Ca2+-activated K+ channels (IKCa) [19,20], and small conductance Ca2+-activated K+ channels (SKCa) [21,22]. The basic scorpion K+ channel toxins (KTxs) are well-known pharmacological tools and potential drug candidates, characterization the acidic KTxs still has the great significance for their potential selectivity towards different K+ channel subtypes. Research on the acidic KTxs has been ignored for several years and progressed slowly
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