364
Cell Junctions, Structure, Function, and Regulation
Aqueous pores
Claudin-1 & -3
Claudin-1 & -2
Transcellular
pathway
Paracellular
pathway
Cld-1
Cld-3
Cld-2
Cld-2
Cld-1
Cld-2
Cld-1
Cld-2
Cld-1
Cld-1
Cld-1
Cld-2
Cld-2
Cld-1
Cld-2
Cld-1
Cld-1
Cld-2
Cld-2
Cld-2
Cld-1
Cld-1
Cld-3
Cld-1
Cld-1
Cld-3
Cld-3
Cld-3
Cld-3
Cld-1
Cld-1
Cld-3
Cld-3
Cld-3
Cld-1
Cld-1
(a)
(b)
TJ strands
Fig. 14
Schematic of proposed model for
paracellular transport through tight junction.
A(a) The claudins are believed to form a strand
containing aqueous pores that acts as a selective
barrier to the flux of molecules between cells
termed paracellular transport. (Bb) Schematic
showing how claudins may interact to form a
selective barrier. (See text for details). (Reprinted
with permission from Tsukita, S., Furuse, M.
(2000) Pores in the wall: Claudins constitute
tight junction strands containing aqueous pores,
J. Cell Biol.
149
, 13–16; Tsukita S., Furuse, M.
2000,
J. Cell Biol.
,
149
, 13–15).
identifed For which mutations in specifc
claudin isoForms were demonstrated to be
the cause oF the underlying pathophysiol-
ogy oF the disease. Indeed, mutations in
claudin 16 (paracellin-1) were identifed
in patients with renal hypomagnesemia,
a rare disease characterized by a massive
urinary loss oF magnesium. Claudin 16
is expressed in the thick ascending limb
in the kidney, a primary site oF magne-
sium uptake. The current thought is that
claudin 16 creates a channel that is selec-
tive For magnesium. This channel would
be absent in patients with claudin 16 mu-
tations; thus, magnesium would remain
in the tubule and be lost in the urine.
Mutations in claudin 14 have been shown
to be responsible For nonsyndromic reces-
sive deaFness. Claudin 14 is located in the
sensory epithelium in the organ oF Corti,
although its exact Function in the inner
ear is not completely understood. Knock-
out animals also provide evidence that
claudins are responsible For the Formation
oF highly selective and tissue-specifc chan-
nels in tight junction strands. Claudin 5 is
a major tight junction protein in endothe-
lial cells with the greatest expression being
Found in the brain vasculature. Claudin
5-null mice were Found to have normal vas-
cular development and showed no change
in the vascular barrier as assessed by
the lack oF edema during development.
However, the transport oF small molecules
(
<
800 Da) was selectively increased in en-
dothelial cells oF the blood-brain barrier
resulting in death 10 h aFter birth. Inter-
estingly, mice lacking claudin 1 die shortly
aFter birth due to dehydration that is the
result oF water loss across the epidermal
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