CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
When architecture matters: a polarized transepithelial I- transport model provides insights into the cell biology, physiology, and transport mechanism of the Na+/I- symporter (NIS)
Autor/es:
PORTULANO, C; REYNA-NEYRA, A; PARODER-BELENITSKY, M; DOHAN, O; BASQUIN, C; NICOLA, JP; MAESTRAS, M; GINTER, CS; ESKANDARI, S; AMZEL, LM; CARRASCO, N
Lugar:
Biddeford, MD
Reunión:
Conferencia; Gordon Research Conference; 2011
Resumen:
The Na+/I-
symporter (NIS)
is the plasma membrane glycoprotein that mediates active I- uptake in the
thyroid gland, lactating breast, and other tissues. NIS-mediated uptake is the
basis for the use of radionuclides for the diagnosis and treatment of thyroid
tumors. However, the majority of thyroid cancers exhibit lowered I- transport
because NIS is
intracellularly retained. To perform its function in vectorial I- accumulation,
NIS is selectively expressed at the (BL) membrane
in all tissues where NIS
function has been investigated. Interestingly, we have shown that the
absorption of dietary I- occurs in the small intestine, where NIS is functionally expressed in the brush
border, i.e., apically, in enterocyte villi. For these reasons, we sought to
study NIS
polarized plasma membrane targeting.
We found that progressive truncations of the intracellular carboxy-terminus
(Ct) reduce NIS
plasma membrane localization and consequently the protein's Vmax for I-
transport, whereas the Km is unaffected. Using an epithelial polarized cell
model, we identified the segment between positions 609 and 611 as an essential
sequence-independent docking site required for NIS BL targeting. These findings
pose new intriguing biological questions about how different epithelia
selectively interpret the polarized sorting signals in the NIS Ct. In addition
to providing a model for investigating the physiology of I- transport, a
transepithelial transport system has the distinctive advantage of allowing
substrate depletion in the compartment where the transporter is targeted, in
contrast to transport experiments in nonpolarized cells, where the
extracellular concentration of the substrate is not significantly altered by
the activity of the transporter. Thus, transepithelial I- transport inhibition experiments enabled us
to uncover that perchlorate (ClO4-), a competitive inhibitor of NIS and an environmental pollutant, is actively
transported by NIS.
Further characterization led to the unprecedented finding that NIS transports different substrates with
different stoichiometries: 2:1 electrogenic for Na+/I- transport and 1:1
electroneutral for ClO4-, suggesting that other transporters may exhibit the
same property. In in vivo experiments, we have shown that NIS also actively concentrates ClO4- in the
lactating mammary gland, thus reducing the availability of I- in the milk,
which is the only source of I- for the newborn, and directly inhibiting I-
uptake in the newborns thyroid. Together with the finding that NIS is functionally
expressed in the intestine, these results indicate that ClO4- exposure due to
water contamination may result in a greater environmental health risk than
previously acknowledged.In summary, the investigation of a cell biology question, i.e., NIS polarized
plasma membrane localization, has provided us with the tools to discover that
NIS actively transports ClO4- with a different stoichiometry than I-, thus
paving the way to studying two very different areas, the mechanism of anion selectivity
and coupling and the public health significance of ClO4- water contamination.