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Henry J. Binder
Professor
of Internal Medicine and
Cellular & Molecular Physiology -
M.D. 1961 New York University
Regulation of colonic
Na transport in apical and basolateral membranes. The
goal of our research program is to further the understanding of the regulation
of colonic electrolyte transport; the clinical expression of these studies is
an increased knowledge of the pathophysiology of and improved treatment for diarrheal
disorders. One area of research is the cellular
mechanisms of active potassium absorptive and secretory processes in the colon.
Primary emphasis at the present time is directed toward active K absorption which
is energized by apical membrane H,K-ATPase, a member of the gene family of P-type
ATPases. The molecular regulation of H,K-ATPase is being actively studied as well
as the mechanism of the enhanced K absorption induced by both aldosterone and
dietary K depletion. The role of basolateral K-Cl cotransport is also critical
in active K absorption. In collaboration with my
colleagues Drs Geibel and Rajendran we also have explored the unique features
of colonic crypt cell function. These studies in the isolated perfused colonic
crypt have established that colonic crypts absorb fluid and Na in the basal state
as a result of a novel Na-H exchange (NHE) that is Cl-dependent (Cl-NHE). This
Cl-NHE is unique and its cloning is in progress. The isolated colonic crypt also
provides a much needed model system to study colonic HCO3 secretion.
Recent studies indicate that colonic HCO3 secretion is closely linked
to Cl secretion but does not involve an apical membrane Cl-HCO3 exchange. A
final area of present interest is the identification of the cellular mechanism
of absorption of short chain fatty acids (SCFA), the primary anion in stool, and
their stimulation of Na-Cl absorption in the colon. SCFA stimulation of Na-Cl
absorption involves an apical membrane mechanism of SCFA uptake (SCFA-HCO3 exchange)
as well as Na-H and Cl-SCFA exchanges. The unexpected failure of cyclic nucleotides
to inhibit SCFA stimulation of Na-Cl absorption led to the hypothesis that starch
that is relatively resistant to pancreatic amylase digestion could serve as an
adjunct to oral rehydration therapy (ORT) in the treatment of diarrhea by enhancing
colonic SCFA production that in turn would result in increased fluid and Na absorption.
This was established in recent clinical trials of patients with cholera at Christian
Medical College in Vellore, India. Further trials are in progress and planned
to establish the optimal resistant starch formulation for ORT and optimal circumstances
for its use. Clinical Interests:
General gastroenterology with particular interest in diarrheal and inflammatory
bowel disease. Selected Publications:
Vidyasagar, S.,
Rajendran, V.M., Binder, H.J.: Three Distinct Mechanisms of HCO3 Secretion in
Rat Distal Colon. Am. J. Physiol. In press. Krishnan,
S., Rajendran, V.M., and Binder, H.J.: Apical
NHE isoforms differentially regulate butyrate-stimulated Na absorption in rat
distal colon. Am. J. Physiol. Cell Physiol. 285:C1246-1254, 2003. Toivola
DM, Krishnan S, Binder HJ, Singh SK, Omary MB: Keratins
modulate colonocyte electrolyte transport via protein mistargeting. J Cell
Biology. 164:911-921, 2004. Robert
ME, Singh SK, Ikuma M, Jain D, Ardito T, Binder HJ. Morphology
of isolated colonic crypts. Cells Tissues Organs. 2001;168(4):246-51.
Rajendran VM, Geibel J, Binder HJ. Characterization
of apical membrane Cl-dependent Na/H exchange in crypt cells of rat distal colon.
Am J Physiol Gastrointest Liver Physiol. 2001 Mar;280(3):G400-5.
Geibel
JP, Rajendran VM, Binder HJ. Na+-dependent
fluid absorption in intact perfused rat colonic crypts. Gastroenterology.
2001 Jan;120(1):144-50.
Rajendran VM, Black J, Ardito TA, Sangan P,
Alper SL, Schweinfest C, Kashgarian M, Binder HJ. Regulation
of DRA and AE1 in rat colon by dietary Na depletion. Am J Physiol Gastrointest
Liver Physiol. 2000 Nov;279(5):G931-42.
Sangan P, Brill SR, Sangan S,
Forbush B 3rd, Binder HJ. Basolateral
K-Cl cotransporter regulates colonic potassium absorption in potassium depletion.
J Biol Chem. 2000 Oct 6;275(40):30813-6. henry.binder@yale.edu | |