TRP Channels and Lysosome Ion Channels in Human Diseases
Calcium signaling is the most common signal transduction mechanism present virtually in any living organisms. Ca(2+) can do everything---essentially from life to death. Therefore, the pathways for Ca(2+) flux must be tightly controlled. The major interest in our lab is to understand how Ca(2+) flux pathways, i.e, Ca(2+)-permeant channels, at the cell surface and in intracellular organelles are precisely controlled (gated) by extracellular and intracellular signals, and how this information is transduced into physiological and pathological changes at the cellular and organismal levels.
We use an integrative approach with state-of-art techniques including molecular biology, bioinformatics, biochemistry, immunochemistry, electrophysiology, fluorescence imaging, spinning-disk confocal microscopy, and mouse genetics. Currently our research is mainly focused on : 1) ion channels in the lysosome, and 2) TRP channels in the skin.
Transient Receptor Potential (TRP) ion channels are a large superfamily (> 28 members for mammals ) of transmembrane proteins serving as molecular/cellular sensors for a variety of physiological/pathological functions. Mammalian TRP channels are organized into six families: classical (TRPC), vanilloid (TRPV), melastatin (TRPM), muclopins (TRPML), polycystin (TRPP), and ANKTM1(TRPA).
Ion Channels in the Lysosome. Lysosomes, traditionally believed to be the terminal “recycle center” for biological “garbage”, are now known to play indispensable roles in numerous cellular processes including intracellular signal transduction and membrane trafficking. Lysosomal (membrane) trafficking is particularly important because lysosomes receive inputs from various of cellular processess, including autophagy , endocytosis, and phagocytosis.
In order to study ion channels in the lysosome, we have recently developed a modified patch-clamp technique to directly record lysosomal membranes, and also established a fluorescence imaging method to specifically measure lysosomal Ca(2+) release using lysosome-targeted Genetically-Encoded Ca(2+) Indicators, such as GCaMP3. Using these approaches, we were able to "open" the gate to the "black box" of the cell's recycling center and discovered several novel ion channels in the lysosome. We are currently characterizing these new lysosome channels and investigating their cell biological functions.
In particular, we found that the mucolipin TRP (TRPML) proteins encode Fe(2+) and Ca(2+) release channels in the membranes of intracellular endosomes and lysosomes. Mutations of human TRPML1 cause type IV mucolipidosis (ML4), a rare but devastating neurodegenerative disease in young children. ML4 patients exhibit motor defects, mental retardation, retinal degeneration, and iron-deficiency anemia. Using TRPML KO and transgenic mice , and with the aid of small molecule TRPML agonists and inhibitors that we have recently identified, we are currently studying the activation mechanisms and in vivo functions of TRPMLs.
TRP Channels in the Skin. Another focus of our current research is TRPV3, a novel Ca(2+)-permeable ion channel that we recently discorvered and is expressed in several sensory tissues (skin, tongue, and sensory neurons). Our in vitro studies suggested several potential sensory fucntions of TRPV3. Human muations of TRPV3 cause Olmsted Syndrome, a rare congenital skin/hair disease. Using TRPV3 KO and transgenic mice, we are currently studying the activation mechanisms and in vivo biological functions of TRPV3, and roles of TRPV3 in skin diseases and hair growth.
