SWELL1 Volume-Regulated Anion Channel (VRAC)
Cell is composed of around 70% water with a plasma membrane also permeable to water. So keeping cell volume constant in response to osmotic challenges is fundamental to life. This is achieved in mammals by maintaining a stable blood plasma osmolarity (near 300 mOsm/L) and by possessing a variety of mechanisms that allow individual cells to monitor and recover their volume following osmotic swelling or shrinkage. Defective osmoregulation leads to various human disorders, including dehydration, hypertension, renal and neurological diseases. However, the identity of many key osmosensing molecules has been a long-standing mystery. Our goal is to elucidate the molecular mechanisms of mammalian osmotic regulation at both the cellular and whole body levels. We performed a genome-wide RNAi screen and discovered SWELL1 (LRRC8A) as an essential component of the elusive Volume-Regulated Anion Channel (VRAC) (Cell, 2014; Cell 2016). VRAC is required for maintaining cell volume in response to osmotic swelling. This discovery enables exciting studies elucidating the function of this important channel in cell volume regulation, fluid secretion, and diseases such as diabetes, stroke and traumatic brain injury. We recently found that SWELL1 channel is a glutamate releasing channel in astrocytes, which modulates synaptic transmission in physiological conditions, and promotes brain damage in stroke (Neuron, 2019).
Deorphanizing the Human Transmembrane Genome: Focus on Novel Ion Channels
The sequencing of the human genome has fueled the last two decades of work to functionally decipher genome content. An important subset (~25%) of genes encodes transmembrane proteins, which represent the targets of over half of known drugs. Despite recent progress, a large number (~1,500) of membrane proteins are still functionally uncharacterized. We focus on deorphanizing a particularly interesting functional class of membrane proteins, i.e. ion channels or transporters, many of which are well characterized biophysically yet lack underlying molecular identity. Toward this end, we are combining the powerful genomics tools (including bioinformatics, proteomics, single-cell RNA sequencing, and RNAi/CRISPR gene manipulation) with electrophysiology and imaging techniques. Our study will shed light on the molecular identity and physiological function of new pore-forming membrane proteins and may provide therapeutic strategies to target them for diseases with abnormal ion transport and homeostasis. As a proof-of-concept, we recently performed another unbiased RNAi screen targeting human multi-spanning transmembrane proteins and identified PAC (also known as TMEM206) as the long-sought acid or proton-activated chloride (PAC) channel, which contributes to acidosis-induced cell death and tissue injury (Science, 2019).