Potential mechanism for differential effects of MTSEA and MTSET modification. In unmodified channels, spermine freely interacts with the D172 carboxylate. In MTSEA-modified 176C channels, MTSEA mimics spermine and competes for strong interactions with the D172 carboxylate. This leads to a reduction in spermine affinity by an indirect mechanism (not by direct overlap with the spermine binding site). MTSET is a quaternary amine and forms much weaker interactions with D172, and therefore does not significantly reduce spermine affinity.