Our research will focus on ion channels in the nervous system, especially in the control of cell signaling pathways, and the structures of the molecules in those pathways.
In July of 2017, the Clapham laboratory moved to the Janelia Research Campus. Here, we will continue work on the ion channels and calcium signals. We have two major interests at present. First, we are interested in the ion channels in primary cilia and how they affect signaling pathways, such as Hedgehog, in embryonic and mature neurons and glia of the hippocampus. We are also pursuing the cryoEM structures of the two main channels of primary cilia so that we can understand their gating.
Second, we are interested in understanding the two unusual ion channels, TRPM7 and TRPM6. These channels are in all cells, and when genetically deleted, are lethal. The channels are unique in that they possess active kinase domains that when cleaved, enter the nucleus and phosphorylate distinct residues on histones that control chromatin accessibility and thus transcription. Answering these questions will require electrophysiology, advanced light microscopy, mouse genetics, and structural approaches.
Primary cilia of CA1 pyramidal neurons (Shu-Hsien Sheu, reconstructed FIB-SEM image)
A cortical neuron, its primary cilia, and glial process (Shu-Hsien Sheu, reconstructed serial section SEM image from Kasthuri et al, Cell, 2015 dataset)
Calcium imaging of primary cilia and immediate cytoplasm (Delling et al, Nature, 2013)
Total internal reflection (TIRF) microscopy of GFP-tagged TRPM7 in live SV40MES-13 cells (Abiria et al, PNAS, 2017)
Primary cilia in the CA3 pyramidal neuron layer (Shu-Hsien Sheu, reconstructed serial section SEM image)