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Mechanisms of Osmotic Regulation in Physiology and Disease
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. To this end, we combine several techniques including high-throughput functional genomics, electrophysiology, mouse genetics, imaging, and biochemistry. For example, we recently performed a genome-wide RNAi screen and co-discovered SWELL1 (LRRC8A) as an essential component of the elusive Volume-Regulated Anion Channel (VRAC). VRAC is required for maintaining cell volume in response to osmotic swelling. Future studies can now address the function and regulation of the ubiquitously expressed VRAC channel in normal and disease states.
Nonomura K, Woo SH, Chang R, Gillich A, Qiu Z, Francisco AG, Ranade SS, Liberles SD, Patapoutian A. (2017) Piezo2 is an airway stretch sensor mediating lung inflation-induced apnea. Nature. 541: 176-181.
Syeda R*, Qiu Z*, Dubin AE, Murthy SE, Florendo MN, Mason DE, Mathur J, Cahalan SM, Peters EC, Montal M, Patapoutian A. (2016) LRRC8 proteins form volume-regulated anion channels that sense ionic strength. Cell. 164: 499-51. *equal contribution.
Qiu Z, Dubin AE, Mathur J, Tu B, Reddy K, Miraglia LJ, Reinhardt J, Orth AP, Patapoutian A. (2014) SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell. 157: 447-458.
Ranade SS*, Qiu Z*, Woo SH, Hur SS, Murthy SE, Cahalan SM, Xu J, Mathur J, Bandell M, Coste B, Li YS, Chien S, Patapoutian A. (2014) Piezo1, a mechanically activated ion channel, is required for vascular development in mice. PNAS. 111: 10347-52. *equal contribution.
Woo SH, Ranade S, Weyer AD, Dubin AE, Baba Y, Qiu Z, Petrus M, Miyamoto T, Reddy K, Lumpkin EA, Stucky CL, Patapoutian A. (2014) Piezo2 is required for Merkel cell mechanotransduction. Nature. 509: 622-6.
Ranade SS, Woo SH, Dubin AE, Moshourab RA, Wetzel C, Petrus M, Mathur J, Bйgay V, Coste B, Mainquist J, Wilson AJ, Francisco AG, Reddy K, Qiu Z, Wood JN, Lewin GR, Patapoutian A. (2014) Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature. 516: 121-5.
Qiu Z, Cang Y & Goff SP. (2010) Abl family tyrosine kinases are essential for basement membrane integrity and cortical lamination in the cerebellum. J Neurosci. 30: 14430-9.
Qiu Z, Cang Y & Goff SP. (2010) c-Abl tyrosine kinase regulates cardiac growth and development. PNAS. 107: 1136-41. PubMed Reference Genander M, Halford MM, Xu NJ, Eriksson M, Yu Z, Qiu Z, Martling A, Greicius G, Thakar S, Catchpole T, Chumley MJ, Zdunek S, Wang C, Holm T, Goff SP, Pettersson S, Pestell RG, Henkemeyer M, Frisйn J. (2009) Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell. 139: 679-692.
Navas-Martin S, Brom M, Chua M, Watson R, Qiu Z, Weiss SR. (2007) Replicase genes of murine coronavirus strains A59 and JHM are interchangeable: differences in pathogenesis map to the 3’ one-third of the genome. J Virol. 81: 1022-6.
Qiu Z, Hingley ST, Simmons G, Yu C, Das Sarma J, Bates P, Weiss SR. (2006) Endosomal proteolysis by cathepsins is necessary for murine coronavirus mouse hepatitis virus type 2 spike-mediated entry. J Virol. 80: 5768-76.
Qiu Z, Xing H, Wei M, Duan Y, Zhao Q, Xu J, Shao Y. (2005) Characterization of five nearly full-length genomes of early HIV type 1 strains in Ruili city: implications for the genesis of CRF07_BC and CRF08_BC circulating in China. AIDS Res Hum Retroviruses. 21:1051-6.