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Na⁺/I^- Symporter Activity Requires a Small and Uncharged Amino Acid Residue at Position 395

Department of Molecular Pharmacology (O.D., M.V.G., C.G., N.C.), Albert Einstein College of Medicine, Bronx, New York 10461; and Department of Biophysics and Biophysical Chemistry (L.M.A.), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Dr. Nancy Carrasco, Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461. E-mail: carrasco{at}aecom.yu.edu.

Active iodide uptake in the thyroid is mediated by the Na⁺/I^- symporter (NIS), a key plasma membrane glycoprotein. Several NIS mutations have been shown to cause I^- transport defect, a condition that, if untreated, can lead to congenital hypothyroidism and, ultimately, cretinism. The study of I^- transport defect-causing NIS mutations provides valuable insights into the structure-function and mechanistic properties of NIS. Here we report the thorough analysis of the G395R NIS mutation. We observed no I^- uptake activity at saturating or even supersaturating external I^- concentrations in COS-7 cells transiently transfected with G395R NIS cDNA, even though we demonstrated normal expression of G395R NIS and proper targeting to the plasma membrane. Several amino acid substitutions at position 395 showed that the presence of an uncharged amino acid residue with a small side chain at position 395 is required for NIS function, suggesting that glycine 395 is located in a tightly packed region of NIS. Substitutions of large amino acid residues at position 395 resulted in lower V_max without affecting K_m values for I^- and Na⁺, suggesting that these residues hamper the Na⁺/I^- coupling reaction.

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