The function of Margatoxin in blocking K+ channels

2018-09-21

Introduction 

Margatoxin (MgTX) is a 39 amino acid peptide with significant sequence homology to charybdotoxin (ChTX), and has such structural motifs as three disulfide bridges, a mid-chain (α-helix), and a C terminal antiparallel β-sheet. This peptide is isolated from the venom of the scorpion Centruroides margaritatus, and is widely used in the field of ion channel research. MgTX is considered as a high affinity and selective inhibitor of the Kv1.3 channel. Potassium channels comprise a family of proteins that have been classified according to their biophysical and pharmacological characteristics. These channels modulate a number of cellular events such as muscle contraction, neuro-endocrine secretion, frequency and duration of action potentials, electrolyte homeostasis, and resting membrane potential.

Biological Activity

Of the channels tested, MgTX potently blocks only Kv1.2 and Kv1.3, members of the Shaker family of coltage-gated potassium (Kv) channels. Kv1.3 has been identified in human, mouse, and rat T cells and it is thought to be responsible for the n-type current recorded in lymphocytes. Kv1.x channels share high sequence homology and tend to form function heterotetrameric structures in different tissues. MgTx is more potent in blocking Kv1.3, Kd of 50 pM in electrophysiological experiments, and has no effect on maxi-K channels nor on the low conductance KCaof lymphocytes at 1 μM. MgTX is 100-fold less sensitive on Kv1.6, and does not affect Kv1.5 or Kv3.1.

Function

K+ channels play a key role in the regulation of the membrane potential of excitable and non-excitable cells. Kv1.3 is a voltage-gated K+channel, which is expressed in a variety of cells and tissues such as the central nervous system, pancreatic islets, lymphocytes, etc. Interestingly, Kv1.3 is the dominant voltage-gated K+ channel of human T-lymphocytes and its expression is sensitively regulated during terminal differentiation of these cells. For example, effector memory T cells (TEM) generated by repeated chronic antigen stimuli express a high number of Kv1.3 as compared to other K+ channels and their proliferation becomes exclusively sensitive to Kv1.3 inhibitors. As TEM cells are responsible for the tissue damage in chronic autoimmune diseases, such as Multiple Sclerosis and Rheumatoid Arthritis, the therapeutic application of Kv1.3 blockers for the inhibition of TEMproliferation is imminent and well-supported in animal models of these diseases. Because of it selectivity for Kv1.3, MgTX has been used to explore the role of this channel in human T lymphocyte activation.

References:

1. Rappuoli, R., & Montecucco, C. (Eds.). (1997). Guidebook to protein toxins and their use in cell biology. OUP Oxford.

2. Bartok, A., Toth, A., Somodi, S., Szanto, T. G., Hajdu, P., Panyi, G., & Varga, Z. (2014). Margatoxin is a non-selective inhibitor of human Kv1. 3 K+ channels. Toxicon, 87, 6-16.

3. Helms, L. M., Felix, J. P., Bugianesi, R. M., Garcia, M. L., Stevens, S., Leonard, R. J & Slaughter, R. S. (1997). Margatoxin binds to a homomultimer of Kv1. 3 channels in Jurkat cells. Comparison with Kv1. 3 expressed in CHO cells. Biochemistry, 36(12), 3737-3744.

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