From cardiac cation channels to the molecular dissection of the transient receptor potential channel TRPM4

In 2006, we celebrate not only the milestone paper on the patch-clamp technique [14] but also the publication of the first single-channel measurements in cardiac cells revealing a Ca²⁺-activated, nonselective cation channel [6]. Considerable effort has been undertaken since this time to identify molecular candidates for this class of cation channels that can be found in a variety of tissues. Recent work has shown that this channel is very likely TRPM4, a member of the TRPM ion channel family. The current review links the epochal Colquhoun et al. paper to the detailed molecular knowledge and structure function aspects of this TRP channel. It will be shown that TRPM4 is a Ca²⁺- and voltage-activated channel, which is dramatically modulated by the phospholipid phosphatidyl inositol bisphosphate (PIP₂) and belongs to the heat-activated thermoTRPs. A functional hallmark of TRPM4, as for several TRP channels, is a dramatic shift of its voltage dependence towards negative, physiologically meaningful potentials.