Intracellular nucleotides and polyamines inhibit the Ca 2+ -activated cation channel TRPM4b

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Abstract
TRPM4b (in contrast to the short splice variant TRPM4a) is a Ca2+-activated but Ca2+-impermeable cation channel. We have studied TRPM4 currents in inside-out patches. Supramicromolar Ca2+ concentrations applied at the inner side, [Ca2+]i, activated TRPM4 with an EC50 value of 0.37 mM, a value that is much higher than that of whole-cell currents. Current amplitudes decreased above 1 mM [Ca2+]i, (IC50 9.3 mM). Sr2+ but not Ba2+could partially substitute for Ca2+. ATP, ADP, AMP and AMP-PNP all quickly and reversibly inhibited TRPM4 with IC50 values between 2 and 19 μM (at +100 mV). Adenosine also blocked TRPM4 at 630 μM. The block at high ATP concentrations was incomplete and was not affected by the presence of free Mg2+. ADP induced the most sensitive block with an IC50 of 2.2 μM. For inhibition of TRPM4 by free ATP4−, an IC50 value of 1.7±0.3 μM was calculated. GTP, UTP and CTP at concentrations up to 1 mM did not induce a similar block. Spermine blocked TRPM4 currents with an IC50 of 61 μM. In conclusion, TRPM4 is a channel that can be effectively modulated by intracellular nucleotides and polyamines.