TRAM-34 inhibits nonselective cation channels

Abstract

TRAM-34 has been demonstrated to inhibit intermediate-conductance Ca(2+)-activated K(+) channels in a wide variety of cell types, including immune cells. In the present study, we investigated effects of TRAM-34 on microglial cells stimulated with lysophosphatidylcholine (LPC). LPC-induced increases in the intracellular Ca(2+) concentration of microglial cells were effectively reduced in the presence of TRAM-34. At a concentration of 1 microM, TRAM-34 inhibited LPC-induced Ca(2+) signals by 60%. The TRAM-34-induced reduction of LPC-induced Ca(2+) increases cannot be related to the inhibition of Ca(2+)-activated K(+) channels. In contrast to TRAM-34, the Ca(2+)-activated K(+) channel inhibitor charybdotoxin did not affect LPC-induced increases in the intracellular Ca(2+) concentration of microglial cells. Patch clamp experiments revealed a direct inhibitory effect of TRAM-34 on nonselective cation channels. Half-maximal inhibition of LPC-induced nonselective cation currents was determined at 38 nM TRAM-34. These data indicate that TRAM-34 may cause additional effects on immune cells that are unrelated to the well-described inhibition of Ca(2+)-activated K(+) channels.