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1 Molecular Physiology Unit, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Tlalpan 14000, Mexico City; and 2 Departamento de Bioquímica, Facultad de Química, Universidad Nacional Autónoma de México, Coyoacán 04510, Mexico City, Mexico
The purpose of the present study was to
determine the major functional, pharmacological, and regulatory
properties of the flounder thiazide-sensitive Na-Cl cotransporter
(flTSC) to make a direct comparison with our recent characterization of
the rat TSC (rTSC; Monroy A, Plata C, Hebert SC, and Gamba G. Am J Physiol Renal Physiol 279: F161-F169, 2000).
When expressed in Xenopus laevis oocytes, flTSC exhibits
lower affinity for Na+ than for Cl
, with
apparent Michaelis-Menten constant (Km) values
of 58.2 ± 7.1 and 22.1 ± 4.2 mM, respectively. These
Km values are significantly higher than those
observed in rTSC. The Na+ and Cl affinities
decreased when the concentration of the counterion was lowered,
suggesting that the binding of one ion increases the affinity of the
transporter for the other. The effect of several thiazides on flTSC
function was biphasic. Low concentrations of thiazides
(109 to 107 M) resulted in activation of
the cotransporter, whereas higher concentrations (106 to
104 M) were inhibitory. In rTSC, this biphasic effect was
observed only with chlorthalidone. The affinity for thiazides in flTSC was lower than in rTSC, but the affinity in flTSC was not affected by
the Na+ or the Cl concentration in the uptake
medium. In addition to thiazides, flTSC and rTSC were inhibited by
Hg2+, with an apparent higher affinity for rTSC. Finally,
flTSC function was decreased by activation of protein kinase C with
phorbol esters and by hypertonicity. In summary, we have found
significant regulatory, kinetic, and pharmacological differences
between flTSC and rTSC orthologues.
metolazone; distal tubule; osmolarity; salt reabsorption; thiazide-sensitive sodium-chloride cotransporter
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