VOL. 3, No. 3/4, October 2006

G. I. Gorodeski [2006] Med Hypotheses Res 3: 769-784.

A New Model of Occludin Regulation of Tight-
junctional Resistance in Low-Resistance

George I. Gorodeski*

Departments of Reproductive Biology, Physiology and Biophysics, and Oncology, Case
Western Reserve University, Cleveland, Ohio, USA

Abstract. Occludin is a transmembrane tight junctional protein whose importance in
gating the intercellular space was recently documented in the low-resistance cultured human
vaginal and cervical epithelia. Decreases in tight-junctional resistance (RTJ) were associated
with occludin degradation, compatible with disassembly of the tight junctions. However,
acute and reversible changes in RTJ could also be induced through modulation of assembled
tight junctions. Thus, lowering extracellular Ca2+ (Ca0) induced an acute and reversible
decrease in RTJ. The present paper presents a novel hypothesis to explain Ca0 modulation of
the RTJ. Accordingly, the functional components of occludin that gate the intercellular space
are occludin extracellular loops. The amino acid sequence of human occludin predicts a
unique composition of the extracellular loops. Tethered within the proximal parts of the
loops are sequences resembling EF-hand – like Ca2+-binding sites. In contrast the distal
parts of the loops are protein stretches enriched with hydrophobic amino acids including
glycine-rich sequences that are typical to proteins that can readily fold. Also, occludin first
and third transmembrane domains from which the loops stem predict α-helices that could
anchor the EF-hands into the plasma membrane, and orient the Ca2+-binding domains
outwards into the extracellular space. The hypothesis predicts that binding of Ca2+ to the EF-
hand – like domains will induce inward folding of the EF-hands, along with envelopment of
the Ca2+-pockets by the hydrophobic distal parts of the loops. Exteriorization of
hydrophobic domains of occludin extracellular loops will lead to formation of hydrophobic
bridges between neighboring cells that effectively occlude the intercellular space.

*Address all correspondence to: Dr. George I. Gorodeski, University MacDonald
Women’s Hospital, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, Ohio
44106. Telephone: 216-844-5977.  Fax: 216-983-0091.  E-Mail:

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