Regulation of TRP channels: A voltage-lipid connection

TRP (transient receptor potential) channels respond to a plethora of stimuli in a fine-tuned manner. We show here that both membrane potential and the level of PI (phosphatidylinositol) phosphates are efficient regulators of TRP channel gating. Recent work has shown that this regulation applies to several members of the TRPV (TRP vanilloid) subfamily (TRPV1 and TRPV5) and the TRPM (TRP melastatin) subfamily (TRPM4/ TRPM5/TRPM7/TRPM8), whereas regulation of members of the TRPC subfamily is still disputed. The mechanism whereby PIP₂ (PI 4,5-bisphosphate) acts on TRPM4, a Ca²⁺- and voltage-activated channel, is shown in detail in this paper: (i) PIP₂ may bind directly to the channel, (ii) PIP₂ induces sensitization to activation by Ca²⁺, and (iii) PIP₂ shifts the voltage dependence towards negative and physiologically more meaningful potentials. A PIP₂-binding pocket seems to comprise a part of the TRP domain and especially pleckstrin homology domains in the C-terminus.