Exploring Structural Relationships between TRP and Kv Channels

Abstract

Transient Receptor Potential (TRP) ion channels are homotetrameric, non-selective cation channels that are expressed in diverse cell types in eukaryotes, ranging from yeast to humans. TRP channels have been implicated in many physiological roles such as thermosensation, mechanosensation, chemesthesis, hearing, and sensing pain. Indeed, TRP channels are gated by a plethora of stimuli. For example, TRPV1 is activated by heat, voltage, and small molecules such as capsaicin, and TRPM8 is activated by cold, voltage and cooling agents such as menthol. The molecular mechanisms underlying this polymodal gating of TRP channels are poorly understood. In contrast, the mechanism of voltage-activation of the voltage-gated potassium (Kv) channels is well understood. The architectural similarity of TRP channels and Kv channels, in addition to several mutagenesis-based reports published on TRP channels, raise the possibility that the mechanisms of voltage gating of these two families of ion channels may have common features. To address this hypothesis, we have created a series of chimeras between the Kv channel, Kv2.1, and two TRP channels, TRPV1 and TRPM8, and studied them using electrophysiological techniques. Replacing the critical S3b-S4 paddle motif of Kv2.1 with analogous regions of TRPV1 or TRPM8, results in channels that activate in response to membrane depolarization. In both instances, the slopes of voltage-activation relations were decreased in the chimeras as compared to wild-type Kv2.1.These results are consistent with the hypothesis that TRP channels contain a structural motif related to the paddle motifs in Kv channels, and that this motif can sense voltage in the context of a Kv channel. We are currently testing whether this motif can sense voltage in TRP channels and exploring structural relationships between these two families of channels.