TRAM-34

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Background

TRAM-34 is a highly selective inhibitor of KCa3.1 channel with IC50 value of 20 nM [1].The Ca (2+)-binding protein calmodulin (CaM) confers Ca (2+) sensitivity to KCa3.1 of KCa3.1. On the basis of crystal structure obtained for the C-terminal region of the rat KCa2.2 channel (rSK2) with CaM that the binding of Ca (2+) to the CaM N-lobe results in CaM interlocking the C-terminal regions of two adjacent KCa3.1 subunits, leading to the formation of a dimeric structure. It is reported that many factors can increase KCa3.1, like balloon injury [2].TRAM-34 is a KCa3.1 channel inhibitor and plays an important role in many diseases. When tested with human T cells, TRAM-34 treatment inhibited cells mobility and migration via blocking KCa3.1 channel [3]. In coronary smooth muscle cells isolated by laser capture microdissection, delivery of TRAM-34 via balloon catheter significantly blocked the KCa3.1 increase [4]. When tested with COS-7 cells, TRAM-34 inhibited KCa3.1 channel with Kd of 20 ± 3 nM and a Hill coefficient of 1.2 with 1 μM calcium in the pipette [1].In male Wistar rat model of ischemic stroke, administration of TRAM-34 intraperitoneal (10 or 40 mg/kg, twice daily) for 7 days reduced infarction, neuronal death, microglia activation and neurological deficit via blocking KCa3.1 channel [5].

[1].Wulff, H., et al., Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proc Natl Acad Sci U S A, 2000. 97(14): p. 8151-6.
[2].Kaushal, V., et al., The Ca2+-activated K+ channel KCNN4/KCa3.1 contributes to microglia activation and nitric oxide-dependent neurodegeneration. J Neurosci, 2007. 27(1): p. 234-44.
[3].Chimote, A.A., et al., Selective inhibition of KCa3.1 channels mediates adenosine regulation of the motility of human T cells. J Immunol, 2013. 191(12): p. 6273-80.
[4].Tharp, D.L., et al., Local delivery of the KCa3.1 blocker, TRAM-34, prevents acute angioplasty-induced coronary smooth muscle phenotypic modulation and limits stenosis. Arterioscler Thromb Vasc Biol, 2008. 28(6): p. 1084-9.
[5].Chen, Y.J., et al., The KCa3.1 blocker TRAM-34 reduces infarction and neurological deficit in a rat model of ischemia/reperfusion stroke. J Cereb Blood Flow Metab, 2011. 31(12): p. 2363-74.