TRPM4 is known to be a non-selective ion channel for monovalent cations activated by increased levels of intracellular Ca²⁺. A dose-response relationship for Ca²⁺ was established for HEK 293 cells overexpressing TRPM4 and insulin-secreting INS-1 cells endogenously expressing TRPM4 by using the whole cell patch-clamp technique (KD = 1.7 - 1.8mM free Ca ²⁺.). Initial outward-rectifying TRPM4 currents and a second phase of linear TRPM4 currents (starting 120s after break in) was recorded, both Ca²⁺ dependent with an additional current increase for the secondary phase triggered by exocytosis. Furthermore it was revealed, that ATP does not influence TRPM4 ion channels. In INS-1 cells 6mM Na-ATP inhibited exocytosis. This was paralleled by the absence of the secondary phase of TRPM4 currents.

In addition, our data indicate that K_ATP and TRPM4 channels are linked by some putative reciprocal regulatory mechanism. This observation and the sensitivity of TRPM4 to Ca²⁺ changes may assign the channel a multifunctional role in insulin-secretion. The Na⁺-influx during the initial phase of TRPM4 activation would support membrane depolarization and with this activation of voltage-operated Ca²⁺ channels. TRPM4 activation of the secondary phase would act as a negative feedback pathway helping to reduce Ca²⁺ influx and reset the system.