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Molecular
and cellular mechanisms and regulation of ion transport by epithelial cells The
maintenance of the ionic content of cells and their environment is vital to life.
We are interested in the structural, biochemical and genetic mechanisms involved
in the regulation of ion transport and signaling by epithelial cells. The movement
of ions through channels is governed by conformational changes resulting in channel
opening or closing, also referred to as gating. Ion channels have evolved an array
of gating sensors. We utilize molecular-genetic, biochemical and pharmacological
approaches to study how nucleotides and protons gate inwardly rectifying K channels.
These K channels play vital roles in kidney, heart, vascular smooth muscle, and
pancreatic ?-cells. In addition, certain ions like calcium can function as extracellular
signaling molecules or "first messengers" by activating a novel G protein-coupled
receptor that we cloned in 1993. This receptor provides the mechanism for extracellular
calcium-mediated regulation of the function of many types of cells. We are studying
the roles of this receptor in epithelial ion and fluid transport, proliferation
and differentiation. This receptor plays important roles in maintaining intestinal
"health" and reducing the risk of colon cancer. Recent
publications: Vanoye,
C.G., MacGregor, G.G., Dong, K., Tang, L.-Q., Hall, A.E., Lu, M., Giebisch, G.
and Hebert, S.C.: The
carboxyl-termini of K(ATP) channels bind nucleotides. J. Biol. Chem. 2002;
277:23260-23270. Lu,
M., Wang, T., Yan, Q., Yang, X., Dong, K., Knepper, M.A., Wang, W., Giebisch,
G., Shull G.E., and Hebert, S.C.: Absence
of small-conductance K+ channel (SK) activity in apical membranes of thick ascending
limb and cortical collecting duct in ROMK (Bartter's) knockout mice. J. Biol.
Chem. 2002; 277:37881-37887. Cheng,
S.X.J., Okuda, M., Hall, A.E., Geibel, J.P. and Hebert, S.C.: Expression
of calcium-sensing receptor in rat colonic epithelium: Evidence for modulation
of fluid secretion. Am. J. Physiol - Gastrointestinal Physiol. 2002; 283:G240-G250.
Loffing
J, Loffing-Cueni D, Valderrabano V, Klausli L, Hebert SC, Rossier BC, Hoenderop
JG, Bindels RJ, Kaissling B. Organization
of the mouse distal nephron: distributions of transcellular calcium and sodium
transport pathways. Am J Physiol Renal Physiol. 2001 Aug 15 [epub ahead of
print]
Riochet DF, Mohammad-Panah R, Hebert SC, MacGregor GG, Baro I
I, Guihard G, Escande D. Inactivating
Properties of Recombinant ROMK2 Channels Expressed in Mammalian Cells. Biochem
Biophys Res Commun. 2001 Aug 17;286(2):376-380.
Plata C, Meade P, Hall
A, Welch RC, Vazquez N, Hebert SC, Gamba G. Alternatively
spliced isoform of apical Na+-K+-Cl- cotransporter gene encodes a furosemide-sensitive
Na+-Cl-cotransporter. Am J Physiol Renal Physiol. 2001 Apr;280(4):F574-82.
Riccardi D, Traebert M, Ward DT, Kaissling B, Biber J, Hebert SC, Murer H.
Dietary
phosphate and parathyroid hormone alter the expression of the calcium-sensing
receptor (CaR) and the Na+-dependent Pi transporter (NaPi-2) in the rat proximal
tubule. Pflugers Arch. 2000 Dec;441(2-3):379-87.
Moral Z, Dong K,
Wei Y, Sterling H, Deng H, Ali S, Gu R, Huang XY, Hebert SC, Giebisch G, Wang
WH. Regulation
of ROMK1 channels by protein-tyrosine kinase and -tyrosine phosphatase. J
Biol Chem. 2001 Mar 9;276(10):7156-63..
steven.hebert@yale.edu
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