TMEM16 membrane protein family in health and disease
Mammalian TMEM16 family comprises ten members. Mutations of human TMEM16 genes have been associated with inherited diseases ranging from bleeding disorder to skeletomuscular disorders and neurological disorders such as dystonia and ataxia. In 2008, the discoveries of TMEM16A and TMEM16B as the long sought-after calcium-activated chloride channels (CaCCs) greatly stimulated the understandings of these largely uncharacterized proteins. Subsequent studies demonstrated that in addition to CaCCs, the TMEM16 family is also comprised of the calcium-activated non-selective channels and the poorly understood calcium-activated lipid scramblases that can quickly translocate phospholipids from one leaflet to the other and destroy their asymmetric distribution on cell membranes in a calcium-dependent manner. Our laboratory aims to understand the biology of TMEM16 proteins at molecular, cellular and system levels using a combination of mouse genetics, biophysical, biochemical and novel imaging approaches.
Structure-Function of TMEM16 proteins
We are interested in understanding three basic properties of TMEM16 proteins: substrate selectivity, activation mechanism and pharmacology. (1) We have shown that instead of being a CaCC, TMEM16F forms a Small-conductance, Calcium-Activated Nonselective (SCAN) channel. Recent studies also suggest that TMEM16F may serve as a calcium-activated lipid scramblase. We will study how TMEM16 proteins selectively transport ions and phospholipids. (2) We identified the calcium binding sites in the TMEM16A-CaCC, which are highly conserved among TMEM16 proteins. We will study how TMEM16 ion channels and lipid scramblases are activated by calcium and other stimuli. (3) We demonstrated that the TMEM16 channels have different pharmacological profiles. We will understand the molecular basis of TMEM16 pharmacology and screen specific and potent pharmacological modulators for TMEM16 proteins.
Physiology of TMEM16 proteins
TMEM16 proteins are expressed in different cell types, including neurons, muscle cells, blood cells, immune cells and epithelial cells. Their physiological and pathological roles remain to be established. We are working on understanding the assembly, trafficking, activation, regulation and function of TMEM16 channels and lipid scramblases in neurons, muscle cells and blood cells. In order to study and manipulate the TMEM16 ion channels and lipid scramblases in various cell types, we will apply and develop molecular sensors and actuators that can monitor and control TMEM16 protein activities in vitro and in vivo. We will also combine mouse genetics, mouse behavioral tests and novel in vivo imaging tools to illustrate the functions of the TMEM16 proteins in the brain.