Mechanisms of Stomatin regulation of Acid-sensing ion channels
We are currently trying to understand how a family of Stomatin-domain containing proteins regulate ASICs. Current evidence suggests that the Stomatin family of proteins interact with ASICs and dramatically reduce their currents in an isoform-dependent manner. We are seeking to understand how Stomatins accomplish this feat.
Lipid regulation of ASICs
Structural mechanisms of proton dependent gating in ASICs
We are using tmFRET and DEER (see research page) to look at how proton binding to a site in the extracellular domain of ASICs leads to the opening of a gate over 50 angstroms away. In the short-term we are asking specific questions about the conformational changes in specific regions of ASIC. In the long term, we would like to use these data to build an overall model for ASIC gating.
Future projects for interested students and postdocs
Are ASICs highly sodium selective channels? Or can they pass calcium as well? What is the mechanism of this selectivity?
This is a critical question for understanding how these channels work at both the structural level, but also at the physiological level. The physiological role of ASICs has often been interpreted through the lens that these channels substantially pass calcium. I think there is mounting evidence that this might not be true. We will work to examine the selectivity of the channels under normal gating as well as during atypical gating conditions such as during toxin binding.
Structural studies of the macromolecular complexes that sense pH which includes ASICs, Stomatins, PSD95, PICK1, and many more proteins.