Professor
General Surgery
Chair of Surgery
Department of Surgery
University of Chicago
5841 S. Maryland Ave., (MC 5029) Chicago, IL 60637
Phone: 773-702-0881
Email:
Education
M.D.: Harvard University, Boston, MA
Fellowship: University of Bern, Bern, Hepatobiliary Surgery
Residency: Beth Israel Hospital, Boston, MA
Fellowship: Brigham and Women's Hospital, Boston, MA Pathology
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EGFP tagged NKCC1 cotransporter internalization after 30 min stimulation whith Phorbol ester in MDCK cells. Unstimulated MDCK cells were shown in the top picture and stimulated cells in the bottom.
Specialized epithelial cells lining the intestine, airway, and exocrine organs secrete an isotonic fluid that lubricates and protects mucosal surfaces. Defective regulation of epithelial fluid and electrolyte secretion underlies a number of diseases ranging from cystic fibrosis to secretory diarrhea The primary mechanism of fluid secretion involves active transcellular transport of chloride (Cl–), accompanied by passive paracellular movement of sodium (Na+) and water as shown in (figure A).
We have established the importance of a basolateral transport protein (the Na-K-2Cl cotransporter NKCC1) in the control of epithelial Cl– secretion. We have identified a novel regulatory mechanism involving alterations in NKCC1 surface expression mediated by protein kinase C (PKC). We are mapping the endocytic pathways of NKCC1 to define the role of specific PKC isoforms associated with NKCC1 internalization.
Other epithelial cells secrete an alkaline fluid enriched in bicarbonate (HCO3–) rather than Cl–. The transport machinery for both Cl– and HCO–3 secretion are present in epithelial cells of the airway, gut, and pancreas. Both the relative amounts of HCO3– vs. Cl– and the total volume of fluid secretion are critical determinants of the properties and composition of mucosal secretions. A model for HCO3– secretion is presented in figure B. It is unclear why some epithelial cell types “choose” to secrete HCO3– preferentially over Cl– (pancreatic duct and duodenocytes) whereas others “choose” Cl– over HCO3– (airway and ileal enterocytes). The mechanism responsible to switch from a Cl– to HCO3– or vice versa upon physiological demand is not understood.
We are currently examining the role of PKC isoforms in the insertion of the Na/HCO3 cotransporter into the basolateral membrane which may account in part for the reciprocal relationship observed between Cl– and HCO3–.
Figure: (A) Chloride secretion model; (B) Bicarbonate secretion
model
Worrell RT, Merk L, Matthews JB. Ammonium transport in the colonic crypt cell line, T84: Role for Rhesus Glycoproteins and NKCC1. Am J Physiol Gastrointest Liver Physiol 2007. (PubMed)
Um JW, Matthews JB, Song JC, Mun EC. Role of protein kinase C in intestinal ischemic preconditioning. J Surg Res 2005; 124(2):289-96 (PubMed)
Worrell RT, Best A, Crawford OR, Xu J, Soleimani M, Matthews JB. Apical ammonium inhibition of cAMP-stimulated secretion in T84 cells is bicarbonate dependent. Am J Physiol Gastrointest Liver Physiol 2005; 289(4):G768-78 (PubMed)
Del Castillo IC, Fedor-Chaiken M, Song JC, Starlinger V, Yoo J, Matlin KS, Matthews JB. Dynamic regulation of Na(+)-K(+)-2Cl(-) cotransporter surface expression by PKC-{epsilon} in Cl(-)--secretory epithelia. Am J Physiol Cell Physiol 2005; 289(5):C1332-42 (PubMed)
Li HC, Szigligeti P, Worrell RT, Matthews JB, Conforti L, Soleimani M. Missense mutations in Na+:HCO3- cotransporter NBC1 show abnormal trafficking in polarized kidney cells: a basis of proximal renal tubular acidosis. Am J Physiol Renal Physiol 2005; 289(1):F61-71 (PubMed)
Mammen JM, Song JC, Yoo J, Kim PS, Davis HW, Calvo MI, Worrell RT, Matlin KS, Matthews JB. Differential subcellular targeting of PKC-epsilon in response to pharmacological or ischemic stimuli in intestinal epithelia. Am J Physiol Gastrointest Liver Physiol 2005; 288(1):G135-42 (PubMed)
Lotz MM, Wang H, Song JC, Pories SE, Matthews JB. K+ channel inhibition accelerates intestinal epithelial cell wound healing. Wound Repair Regen 2004; 12(5):565-74 (PubMed)
Prahalad P, Calvo I, Waechter H, Matthews JB, Zuk A, Matlin KS. Regulation of MDCK cell-substratum adhesion by RhoA and myosin light chain kinase after ATP depletion. Am J Physiol Cell Physiol 2004; 286(3):C693-707 (PubMed)
Li HC, Worrell RT, Matthews JB, Husseinzadeh H, Neumeier L, Petrovic S, Conforti L, Soleimani M. Identification of a carboxyl-terminal motif essential for the targeting of Na+-HCO-3 cotransporter NBC1 to the basolateral membrane. J Biol Chem 2004; 279(41):43190-7 (PubMed)
Worrell RT, Oghene J, Matthews JB. Ammonium effects on colonic Cl- secretion: anomalous mole fraction behavior. Am J Physiol Gastrointest Liver Physiol 2004; 286(1):G14-22 (PubMed)
Del Castillo IC, Alvarez JG, Freedman SD, Ollero M, Claros L, Song JC, Yoo J, Matthews JB. Docosahexaenoic acid selectively augments muscarinic stimulation of epithelial Cl- secretion. J Surg Res 2003; 110(2):338-43 (PubMed)
Yoo J, Nichols A, Mammen J, Calvo I, Song JC, Worrell RT, Matlin K, Matthews JB. Bryostatin-1 enhances barrier function in T84 epithelia through PKC-dependent regulation of tight junction proteins. Am J Physiol Cell Physiol 2003; 285(2):C300-9 (PubMed)
Lotz M, Wang HH, Cance W, Matthews J, Pories S. Epidermal growth factor stimulation can substitute for c-Src overexpression in promoting breast carcinoma invasion. J Surg Res 2003; 109(2):123-9 (PubMed)
Yoo J, Nichols A, Song JC, Mammen J, Calvo I, Worrell RT, Cuppoletti J, Matlin K, Matthews JB. Bryostatin-1 attenuates TNF-induced epithelial barrier dysfunction: role of novel PKC isozymes. Am J Physiol Gastrointest Liver Physiol 2003; 284(4):G703-12 (PubMed)
Matthews JB. Molecular regulation of Na+-K+-2Cl- cotransporter (NKCC1) and epithelial chloride secretion. World J Surg 2002; 26(7):826-30 (PubMed)
