Aim 1. Decoding GPCR Conformational Dynamics and Biased Signaling for Disease-Specific Therapeutic Targeting

Our lab investigates the real-time conformational dynamics of G protein-coupled receptors (GPCRs), specifically the M3 muscarinic receptor (M3R). Using advanced FRET-based sensors, we have uncovered the sequential structural transitions of M3R driven by the Gq protein cycle and identified distinct, kinase-specific binding modes of β-arrestin. Building on these insights, our future research will focus on mapping the spatiotemporal regulation of GPCR-effector complexes in living cells. By integrating these findings, we aim to elucidate how specific receptor "barcodes" and lipid-mediated environments fine-tune signaling outcomes, ultimately providing a framework for developing precise, pathway-selective therapeutic interventions for complex neurological disorders.

Aim 2. Molecular Mechanisms of Ion Channel Modulation by Phosphoinositides in Neuronal Excitability 

This research aims to elucidate the molecular mechanisms by which membrane phosphoinositides regulate neuronal voltage-gated Ca2+ channels and KCNQ K+ channels. By employing novel tools for the rapid, real-time manipulation of phosphoinositides, we will investigate how lipid-mediated signaling modulates ion channel activity and governs neuronal excitability and synaptic transmission. Our study will bridge the gap between lipid metabolism and channel physiology, providing critical insights into the pathophysiology of neurological disorders, such as epilepsy and pain. Ultimately, these findings will establish a foundational framework for developing targeted therapeutic strategies that modulate membrane lipid-ion channel interactions to treat complex neurological diseases.

Aim 3. Lipid Scramblase and Macropinocytosis: For Plasma Membrane Integrity

This research aims to elucidate the molecular dynamics linking TMEM16-mediated phospholipid scrambling to plasma membrane repair. We will investigate how TMEM16 triggers ligand-independent growth factor receptor activation, subsequently driving PI3K-dependent macropinocytosis. By characterizing the reciprocal relationship between scramblase activity and membrane internalization, we will demonstrate how this endocytic pathway serves as a protective mechanism to restore membrane asymmetry and integrity under physiological stress. These findings will provide critical insights into the role of TMEM16E in cellular survival, offering a mechanistic framework for understanding pathologies associated with compromised membrane repair, such as muscular dystrophies and bone disorders.

Aim 4. Deciphering the Lipid-Channel Interactome: Functional Lipidomics on Ion Channel Modulation [기초연구실 BRL 사업] 

This research aims to bridge the gap between lipidomic profiling and ion channel physiology by investigating the functional impact of the membrane lipid environment on channel gating and signaling. Utilizing advanced mass spectrometry-based lipidomics combined with electrophysiological and optogenetic tools, we will map the specific lipid-protein interactions that govern ion channel activity in living cells. Our goal is to identify key lipid species that act as allosteric modulators, elucidating how localized lipid microdomains regulate channel function. These findings will provide fundamental insights into the lipid-mediated control of neuronal excitability and offer novel therapeutic targets for lipid-related channelopathies and neurological disorders.