CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
From dietary iodide absorption to Na+/I- symporter (NIS) transport stoichiometry and substrate specificity
Autor/es:
NICOLA, JP; PARODER-BELENITSKY, M; MAESTRAS, M; DOHAN, O; REYNA-NEYRA, A; FOLLENZI, A; DADACHOVA, E; ESKANDARI, S; AMZEL, LM; CARRASCO, N
Lugar:
Biddeford, MD
Reunión:
Conferencia; Gordon Research Conference; 2011
Resumen:
The Na+/I-
symporter (NIS) is an integral plasma membrane
glycoprotein commonly discussed in connection with the thyroid gland, where NIS mediates the active
transport of iodide into the thyroid follicular cells, the crucial first step in
the biosynthesis of the only iodine-containing hormones in vertebrates, the
thyroid hormones. NIS
is basolaterally expressed in the thyroid and in many other tissues, including
lactating breast, salivary glands, and gastric mucosa.
Iodine is
extremely scarce in the environment and can only be obtained through the diet. Therefore,
dietary iodide absorption in the gastrointestinal tract constitutes the first
step in iodide metabolism. The question of where and how dietary iodide is
absorbed has long been of major interest. We have identified functional NIS expression along the
entire length of the small intestinal epithelium, and postulated it as the
central component of the iodide absorption system. Interestingly, NIS expression was clearly apparent exclusively on the
apical surface of the enterocytes (in contrast to the basolateral expression in
the aforementioned tissues), consistent with the notion that NIS may transport iodide from the intestinal
lumen towards the bloodstream.
Under
physiological conditions, NIS
concentrates iodide by coupling the inward transport of Na+ down its
electrochemical gradient to the translocation of I- against its
electrochemical gradient. NIS-mediated transport of iodide is electrogenic,
coupling the transport of 2 Na+ cations and 1 I- anion. We
have recently shown that NIS
translocates different substrates with different stoichiometries, as NIS-mediated
transport of perrhenate (ReO4-) or the environmental
pollutant perchlorate (ClO4-) is electroneutral. Mechanistic
information has been obtained by characterizing congenital I-
transport defectcausing NIS
mutants. One of these, G93R NIS, is targeted to the plasma membrane but is
inactive, and led us to conduct a detailed study of position 93. We observed
that the longer the side chain of the neutral residue substituted at this
position, the lower the activity of the protein, and the higher the Km for the anion substrates.
Strikingly, unlike NIS,
which mediates electroneutral Na+/ReO4- or ClO4-
symport, G93T NIS transports these anions electrogenically with a 2:1
stoichiometry. Surprisingly, although G93E NIS exhibited no apparent I-
transport activity, it clearly exhibited ReO4- transport,
suggesting that this position can discriminate substrates. Based on the 3-D
structure of the bacterial Na+/galactose transporter, we built a 3-D
homology model of NIS
and propose a mechanism in which changes from an outwardly to an inwardly open
conformation during the transport cycle use G93 as a pivot.