Structural Insights into the Function of TRP Channels

This chapter reviews our knowledge of the three-dimensional structure of TRP channels and how this information relates to channel function and regulation. Sequence analyses have revealed the domain composition of TRP channels. Because no structure has been determined for a complete TRP channel, I will first break down TRP channels into component parts, or building blocks, and then discuss the structural information available for each, using the closest sequence homologues for which structures have been determined. TRP channels are part of the same channel superfamily as the voltage- and ligand-gated potassium channels [1]. Because the highest sequence similarity between these and TRP channels is found in the transmembrane domain, all TRP channels are expected to form tetramers—homo- or heterotetramers—as functional units, like the voltage- and ligand-gated channels. Biochemical and biophysical analyses have confirmed that several TRP channels are indeed tetrameric (e.g., see reference [2]). The transmembrane domain of each TRP channel subunit is expected to contain six roughly membrane-spanning helical segments, S1 to S6—and therefore both the N-and C- terminal extensions are cytosolic. The transmembrane domain can be divided in two building blocks: the sensor, formed by helices S1–S4, and the pore, formed by helices S5 and S6. The pore forms a hole that spans the lipid membrane and passes ions and other hydrophilic molecules, to which the lipid membrane is otherwise impermeable. The pore contains a selectivity filter, the smallest constriction of pore, which dictates through its stereochemical and electrostatic properties what kind of molecules are allowed through the pore. The sensor perceives the signal(s) and transmits the information to the gate, the channel component that opens or closes the pore. The cytosolic domains of TRP channels contain regulatory components that can tune the channel opening propensity in a positive or negative fashion. Perhaps some of the most intriguing structural aspects of TRP channels are the diversity of their cytosolic domains. The TRP channel family is divided into seven subfamilies based on sequence similarity and function, and there is little homology in the N- and C-terminal cytosolic regions between subfamilies. Furthermore, while some common protein–protein interaction motifs can be identified in the cytosolic regions, such as ankyrin repeats, calmodulin-binding sites and PDZ domain–binding sites, other cytosolic segments appear novel by sequence analysis. The following sections highlight the current structural information on the TRP channel building blocks within the transmembrane region and the cytosolic domains.