|Department Affiliations||Medicine (GI), Physiology|
|Rank||Professor, Director, Hopkins Center for Epithelial Disorders, Director, Hopkins NIH Conte Digestive Diseases Basic & Translational Research Core Center|
|SOM Address||925 Ross|
Study of two gene families initially recognized by this laboratory: mammalian Na/H exchangers and subgroup of PDZ domain containing proteins present in the brush border of epithelial cells called NHERF family. Study of two areas are ongoing. The role of PDZ domain proteins in regulation of the epithelial brush border Na/H exchanger NHE3. Short term stimulation and inhibition of NHE3 occur as part of normal digestion and in diarrheal diseases in which normal signal transduction is taken over by agents that produce diarrhea to alter NHE3 activity. Brush border PDZ domain proteins normally present in the brush border are involved in rapid regulation of NHE3. Specific mechanisms involved are being examined and include stimulation of exocytosis and of endocytosis. Attachment of NHE3 to the cytoskeleton is required for this regulation and the role of cytoskeleton in NHE3 regulation is being studied using physical techniques such as fluorescence recovery after photobleaching. Why only specific PDZ domain proteins are needed for specific forms of NHE3 regulation has revealed that the NHERF protens functon as heterodimers which set the brush border mobility of NHE3. A major finding is that NHE3 exists simultaneously in different sized complexes in the brush border which change separately as part of signal transduction initiated by mimics of the digestive process. Relevance to human intestine is being pursued using mini-human intestine made from Lgr5+ stems cells made from intestinal biopsies and measuring function via two photon microscopy.
- Mahon, MJ, Donowitz M, Segre GV. Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signaling. Nature. 417:458-461, 2002.
- Zhu X, Cha B, Zachos NC, Sarker R, Chakraborty M, Chen TE, Kovbasnjuk O, Donowitz M. Elevated calcium acutely regulates dynamic interactions of NHERF2 and NHE3 proteins in opossum kidney (OK) cell microvilli. J Biol Chem. 286:34486-34496, 2011. PMC3186394
- Yang J, Donowitz M, Tse CM, Fuster D. SLC9 or NHE gene family, a plasma membrane and organellar family of Na/H antiporters. Journal Mol Aspects Med. 34:236-251, 2012. PMC3724465.
- Zizak M, Bartonicek D, Sarker R, Chen T, Zachos N, Cha B, Kovbasnjuk O, Korac J, Mohan S, Cole R, Chen Y, Tse CM, Donowitz M. Calmodulin kinase II constitutively binds, phophorylates, and inhibits the brush border Na+/H+ exchanger NHE3. J Biol Chem. 287:13442-13456, 2012. PMC3340005.
- Yang J, Singh V, , Cha B, Chen TE, Sarker R, Murtazina R, Jin S, Zachos, NC, Patterson GH, Tse CM, Kovbasnjuk O, Li X, Donowitz M NHERF2 Mobility Rate is Determined by a Unique C-Terminal Domain that is Also Necessary for its Regulation of NHE3 in OK Cells. J Biol Chem. 288:10960-10971, 2013. PMC3675628