Grandl Laboratory

Ion channels can be activated (gated) by various stimuli (e.g. chemicals, voltage, pressure and temperature). Whereas the mechanisms of ion channel gating by chemicals or voltage are understood in principal, the logic of ion channel activation by temperature and mechanical stimulation has remained elusive. We use a combination of high-throughput mutagenesis screens and electrophysiology to identify mechanisms of ion channel function.



Temperature-Activated Ion Channels
A subset of transient receptor potential ion channels, called thermoTRPs, is expressed in sensory neurons and activated by cold or hot temperatures with distinct temperature-thresholds. They are also activated by sensory chemicals such as capsaicin, the active ingredient in hot chili peppers or menthol found in mint plants. TRP channels have been shown to be the principal receptors of temperature in vivo and sensors of chemical pain and inflammatory pain. Unsurprisingly, TRP channels have received much attention as pharmaceutical targets, but development of efficient and specific drugs is hindered by the limited knowledge of their structure and function. The goal of this lab is to identify the structures and mechanism that underlies temperature-activation.

Mechanically-activated Ion Channels
Surprisingly, the molecular identity of mammalian touch-sensors is unknown. Very recent work has identified a novel gene family (Piezos) that induces mechanical-sensitive cationic currents to various cell types, which makes them promising candidates for the elusive touch-sensor. Piezos are extremely large proteins with 24-36 predicted transmembrane domains. Piezos are conserved throughout evolution, but share no homology to any known ion channel family. How Piezos induce mechanical-sensitivity is unknown. We aim to understand the activation-mechanism of this novel gene family.



G. Pitt

Jorg Grandl, PhD
DUMC 103030
Durham, NC 27710
(919) 684-1144