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Molecular
physiology of membrane transporters.
Regulation of intracellular ion concentrations
is essential to all living cells. The transport of ions mediated by
specific membrane proteins underlies control of cell volume, epithelial
transport, and the maintenance of transmembrane ion gradients which
underlie electrical activity in nerve and muscle cells. Work in this
laboratory is directed towards understanding the mechanisms by which
transmembrane ion transport take place, and our attention is focused
on a particular membrane transport system, the Na-K-Cl cotransporter.
This cell membrane protein uses the Na gradient to drive accumulation
of cellular K and Cl. The transporter is a central element in the process
of net salt transport in both secretory and absorptive epithelia. In
order to begin to understand the workings of the transporter, we have
cloned the cDNAs from human colon and from rabbit kidney and have prepared
monoclonal antibodies to the protein. Currently we are addressing questions
of structure-function relationships and of protein kinase-mediated regulation
using a system in which the cDNAs for the Na-K-Cl cotransporter are
expressed in mammalian cell lines.
Figure caption:
A model of the human Na-K-Cl cotransporter
(hNKCC1) Topological model based on hydropathy analysis and on data
regarding the position of glycosylated, phosphorylated, and antigenic
residues. Residues which are identical between the human and shark (sNKCC1)
cotransporters are shown in red.
Recent publications:
Darman
RB, Flemmer A, Forbush B. Modulation
of ion transport by direct targeting of PP1 to the Na-K-Cl cotransporter.
J Biol Chem. 2001 Jul 20
Haas M, Forbush B 3rd. The
Na-K-Cl cotransporter of secretory epithelia. Annu Rev Physiol.
2000;62:515-34. Review.
Gillen CM, Forbush B 3rd. Functional
interaction of the K-Cl cotransporter (KCC1) with the Na-K-Cl cotransporter
in HEK-293 cells. Am J Physiol. 1999 Feb;276(2 Pt 1):C328-36.
Isenring P, Jacoby SC, Chang J, Forbush B. Mutagenic
mapping of the Na-K-Cl cotransporter for domains involved in ion transport
and bumetanide binding. J Gen Physiol. 1998 Nov;112(5):549-58.
bliss.forbush@yale.edu
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