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2017 ; 114
(2
): E219-E227
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English Wikipedia
Mosaic expression of claudins in thick ascending limbs of Henle results in
spatial separation of paracellular Na+ and Mg2+ transport
#MMPMID28028216
Milatz S
; Himmerkus N
; Wulfmeyer VC
; Drewell H
; Mutig K
; Hou J
; Breiderhoff T
; Müller D
; Fromm M
; Bleich M
; Günzel D
Proc Natl Acad Sci U S A
2017[Jan]; 114
(2
): E219-E227
PMID28028216
show ga
The thick ascending limb (TAL) of Henle's loop drives paracellular Na(+), Ca(2+),
and Mg(2+) reabsorption via the tight junction (TJ). The TJ is composed of
claudins that consist of four transmembrane segments, two extracellular segments
(ECS1 and -2), and one intracellular loop. Claudins interact within the same
(cis) and opposing (trans) plasma membranes. The claudins Cldn10b, -16, and -19
facilitate cation reabsorption in the TAL, and their absence leads to a severe
disturbance of renal ion homeostasis. We combined electrophysiological
measurements on microperfused mouse TAL segments with subsequent analysis of
claudin expression by immunostaining and confocal microscopy. Claudin interaction
properties were examined using heterologous expression in the TJ-free cell line
HEK 293, live-cell imaging, and Förster/FRET. To reveal determinants of
interaction properties, a set of TAL claudin protein chimeras was created and
analyzed. Our main findings are that (i) TAL TJs show a mosaic expression pattern
of either cldn10b or cldn3/cldn16/cldn19 in a complex; (ii) TJs dominated by
cldn10b prefer Na(+) over Mg(2+), whereas TJs dominated by cldn16 favor Mg(2+)
over Na(+); (iii) cldn10b does not interact with other TAL claudins, whereas
cldn3 and cldn16 can interact with cldn19 to form joint strands; and (iv) further
claudin segments in addition to ECS2 are crucial for trans interaction. We
suggest the existence of at least two spatially distinct types of paracellular
channels in TAL: a cldn10b-based channel for monovalent cations such as Na(+) and
a spatially distinct site for reabsorption of divalent cations such as Ca(2+) and
Mg(2).