Understanding ion channel proteostasis
My laboratory aims to understand ion channel protein homeostasis (proteostasis) in vivo. We focus on studying gamma-aminobutyric acid type A (GABAA) receptors and potassium channels, KCNH2. Mutations in ion channels can lead to protein misfolding and extensive ER-associated degradation (ERAD), causing ion channel diseases, such as idiopathic epilepsy and cardiac arrhythmias, due to a lowered concentration of ion channels in cell membranes and thus loss of function. We explore how molecular chaperones, folding enzymes and other important protein factors coordinate to facilitate ion channel folding, degradation and trafficking. We also use small molecules to correct misfolded ion channels, as a therapeutic strategy to treat epilepsy and cardiac arrhythmias.
GABAAR protein homeostasis in the cell
GABAA receptors maintain a delicate balance between protein synthesis, folding, trafficking and degradation. Mutations in GABAA receptors resulted in extensive endoplasmic-reticulum associated degradation. Molecular chaperones and ERAD factors play a key role in regulating GABAA receptor proteostasis in the cell.
Understanding the Molecular Mechanism of Ion Channel Folding in the Cell.
Because ion channel structures are extremely difficult to determine and their activity is coupled to other proteins in complicated cellular interaction networks, the molecular mechanism of ion channel folding in the cell has been elusive. Using representative members from both the ligand-gated ion channel family, such as GABAA receptors, and the voltage-gated ion channel family, such as KCNH2 potassium channels, we aim to reveal the protein homeostasis network that control ion channel folding and trafficking using proteomics and cell biological techniques.
Ameliorating Ion Channel Misfolding Diseases.
Aberrant ion channel functions lead to diseases called channelopathies. We focus on channelopathies resulting from protein misfolding and thus reduced receptor surface expression and compromised function. This defective protein trafficking has been reported to result in many channelopathies including epilepsy and cardiac arrhythmias. Epilepsy is a common neurological disease that affects 1% of the population in the United States. We focus on developing multiple strategies to discover small molecules that enhance proper ion channel folding to ameliorate epilepsy. We also explore the mechanism of action of these small molecules: how they alter the signaling pathways associated with the protein homeostasis network for disease intervention. Ultimately, we aim to develop novel therapeutic strategies for channelopathies resulting from protein misfolding.
- Di XJ, Han, DY, Wang, YJ, Chance, MR, Mu, TW (2013) SAHA enhances proteostasis of epilepsy-associated α1(A322D)β2γ2 GABAA receptors. Chemistry and Biology, http://dx.doi.org/10.1016/j.chembiol.2013.09.020.
- Wang, YJ, Han, DY, Tabib, T, Yates, JR, and Mu, TW (2013) Identification of GABAC receptor protein homeostasis network components from three tandem mass spectrometry proteomics approaches. Journal of Proteome Research, http://dx.doi.org/10.1021/pr400535z.
- Ong DS, YJ Wang, YL Tan, JR Yates*, TW Mu* & JW Kelly*. FKBP10 depletion enhances glucocerebrosidase proteostasis in Gaucher disease fibroblasts. Chem. Biol. 20:403-15, 2013. * corresponding author
- Mu TW, DS Ong, YJ Wang, WE Balch, JR Yates, L Segatori & JW Kelly.Chemical and biological approaches synergize to ameliorate protein-folding diseases. Cell 134:769-81, 2008.
- Mu TW, HA Lester & DA Dougherty.Different binding orientations for the same agonist at homologous receptors: a lock and key or a simple wedge? J. Am. Chem. Soc. 125:6850-1, 2003.