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Molecular Regulation

Molecular Regulation and Physiological/Pathophysiological Role of Chloride Channel 5 (Clc-5) and Na/H Exchanger 3 (NHE3)

Principal Investigator

Xuhang Li, Ph.D.

Research team

Douglas Adler, M.S.
Jin Shi, Ph.D.
Angela Yang, M.D./Ph.D.
Xiaoou Yang, M.D.

Contact Information

Xuhang Li, Ph.D.
Assistant Professor of Medicine
Johns Hopkins University School of Medicine
Department of Medicine
746 Ross Research Bldg, 720 Rutland Ave.
Baltimore, M.D. 21205
Phone: 443-287-4804 (Office)
410-502-4487 (Lab-1)
410-502-4581 (Lab-2)
Fax: 410-955-9677

Study Focus

Both NHE3 and Clc-5 are most abundantly expressed in the kidney and small intestine. NHE3 is an epithelial plasma membrane transporter responsible for intestinal and renal neutral Na absorption. Clc-5, an intracellular Cl-/H+ exchanger, is thought to play an important role in regulating vesicular luminal pH and the apical trafficking of intestinal and renal neutral epithelial cells. Mutations in CLC-5 in human or Clc-5 knockout (KO) mice develop a kidney disease called Dent’s disease.

We have shown recently that in patients with active IBD, both NHE3 and ClC-5 are down regulated, implying a potential mechanism of diarrheal mechanism in IBD. We have also demonstrated that Clc-5 KO mice are more susceptible to DSS-induced colitis. In the small intestine, NHE3 inhibition is a major mechanism for most diarrheal diseases. Preliminary data indicate that Clc-5 may directly or indirectly regulate NHE3 trafficking. Therefore understanding the regulatory mechanisms of Clc-5 and NHE3 is of great significance in gastrointestinal and renal physiology.

Nearly all known acute regulations of NHE3 are mediated by its cytosolic C-terminus, which we have demonstrated to form large dynamic multi-protein complexes, ranging from 300 kDa to 1000 kDa. We postulated that a dynamic interaction of the NHE3 C-terminus with different regulatory proteins regulate NHE3 activity. By proteomic approach, we recently identified a new NHE3-associated regulatory protein, casein kinase 2 (CK2) that is involved in the controlling NHE3 activity.

Current research aims to:

  • Determine how NHE3 C-terminus plays a role in NHE3 regulation and dictates NHE3 trafficking
  • Investigate the role of Clc-5 in regulating membrane trafficking, mucosal inflammation and nutrient absorption in the intestine
  • Identify novel regulatory factors that dynamically interact with the NHE3 and Clc-5 using proteomic approach
  • Investigate molecular and functional relationship between Clc-5 and NHE3 in the intestine

Publications

  1. Lin, R., Murtazina, R., Cha, B., Chakraborty, M., Sarker, R., Chen, T., Lin, Z., Hogema, B. M., deJonge, Seidler, U., Turner, J. R., Li, X., Kovbasnjuk, O., Donowitz, M. 2011. D-Glucose Acts via SGLTI to Increase NHE3 in Mouse Jejunal Brush Border by a NHERF2-Dependent Process. Gastroenterology. 140 (2): 560-71
  2. Donowitz, M., Singh, S., Singh, P., Chakraborty, M., Chen, Y., Murtazina, R., Gucek, M., Zachos, N.C., Salahuddin, F.F., Kavbasnjuk, O., Broere, N., Smalley-Freed, W.G., Reynolds, A.B., Hubbard, A.L., Seidler, U., Weinman, E., de Jonge H.R., Li, X. 2011. Alternations in the proteome of the NHERF2 knockout mice jejunal brush border membrane vesicles. Physiol Genomics. 43 (11): 674-84
  3. Donowitz, M, Singh, S, Singh, P., Salahuddin, FF, Chen, Y, Chakraborty, M., Gucek, M., Cole, R.N., Ham, A., Zachos, N.C., Kovbasnjuk, O., Lapierre, L.A., Broere, N., Smalley, W.G.,  Reynolds, A.B., Hubbard, A.L., Goldenring, J., Seidler, U., de Jonge, H., R. Murtazina, Hogema, B.M., and Li, X. 2010. Alterations in the Proteome of the NHERF1 Knockout Mouse Jejunal Brush Border Membrane Vesicles. Physiol Genomics. 42A (3): 200-10
  4. Alex, P., Ye, M., Sipes, J., Nguyen,  T., Gonzales, L., Saksonov-Suhodrev, M., Zhang, T., Arora, Z., Centola, M., Guggino, S.E., Li,  X. 2010. Clc-5 Knockout Mice Are More Susceptible to Dextran Sulphate Sodium Induced Colitis. Journal of Immunology. 187, 3988-3996
  5. Sullivan, S., Alex P., Dassopoulos, T., Zachos, N.C., Iacobuzio-Donahue, C., Donowitz, M., Brant, S.R., Cuffari, C., Harris, M.L., Datta L.W., Conklin, L., Chen, Y., and Li, X. 2009. Down-Regulation of Sodium Transporters and NHERF Proteins in IBD Patients and Mouse Colitis Models: Potential Contributors to IBD-associated Diarrhea. Inflammatory Bowel Disease. 15(2), 261-274
  6. Sarker, R., Grønborg, M., Cha, B., Chen, Y., Mohan, S., Pandey, A., Litchfield, D., Donowitz, M. and Li, X. 2008. CK2 Binds to the C-Terminus of NHE3 and Stimulates NHE3 Basal Activity by Phosphorylating a Separate Site. Mol. Biol. Cell. 19(9), 3859-3870
  7. Donowitz, M., Singh, S., Salahuddin, F. F., Hogema, B. M., Gucek, M., Cole, R. N., Chen, Y., Zachos, N., Kovbasnjuk, O., Lapierre, L., Broere, N., Goldenring, J., deJonge, H. Li, X.  2007. Proteome of the Murine Jejunal Brush Border. Journal of Proteome Research. 6 (10), 4068-4079
  8. Donowitz, M and Li, X. 2007. Regulatory binding partner and complexes of NHE3. Physiological Review. 87 (3), 825-72
  9. Murtazina, R., Kovbasnjuk, O., Donowitz, M., and Li, X. 2006. Na+/H+ exchanger 3 activity and trafficking are lipid raft dependent. J. Biol. Chem. 281, 17845-17855
  10. Li, X., Leu, S., Birnbaum, M. J., Baibakov, B., Zhang, H., Shih, C. and Donowitz, M. 2004. Akt, PI-3 Kinase and PTEN are in lipid rafts in brush border of intestinal epithelial cells: potential involvement of Akt2 in stimulated Na absorption and differentiation. Gastroenterology. 126, 122-35
 

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