Dr. Cheng is interested in the structure and function of neuronal ligand-gated ion channels, and the mechanism of channel modulation by endogenous lipids or exogenous drugs such as general anesthetics.
The mammalian cell membrane consists of a heterogenous and dynamic collection of lipids that are important in cell signaling. Neuronal ligand-gated ion channels (LGICs) are expressed within this complex membrane, and are key targets of neuroactive drugs, including general anesthetics and analgesics. Changes in the lipid content of neuronal membranes are fundamentally important in normal and pathologic processes, such as chronic pain and psychiatric diseases, and may also determine sensitivity to drugs such as anesthetics. Moreover, lipids such as steroids, polyunsaturated fatty acids (PUFAs), and phosphoinositides are themselves allosteric modulators of LGIC activity, and have the potential to become novel therapeutics. How various lipids interact with LGICs, and whether lipids alter the binding and effect of other drugs in LGICs is poorly understood.
The overarching goal of Dr. Cheng’s research program is to understand the structural basis of specific lipid binding interactions with LGICs such as the GABA(A) receptor and nicotinic acetylcholine receptor, and to assess the role of these binding events on LGIC pharmacology and function. To pursue this, the Cheng lab utilizes a combination of biochemical and biophysical approaches including native ion mobility mass spectrometry, photo-affinity labeling, electrophysiology, cryoEM, and molecular modeling. The long-term goal of this research is to develop detailed structural models of lipid or allosteric modulation of membrane proteins that will inform the design of novel therapeutics.