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J Biol Chem, Vol. 273, Issue 37, 23884-23891, September 11, 1998
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From the Loss of function mutations in kidney Kir1.1
(renal outer medullary potassium channel, KCNJ1) inwardly
rectifying potassium channels can be found in patients suffering from
hyperprostaglandin E syndrome (HPS), the antenatal form of Bartter
syndrome. A novel mutation found in a sporadic case substitutes an
asparagine by a positively charged lysine residue at amino acid
position 124 in the extracellular M1-H5 linker region. When
heterologously expressed in Xenopus oocytes and mammalian
cells, current amplitudes from mutant Kir1.1a[N124K] channels were
reduced by a factor of ~12 as compared with wild type. A lysine at
the equivalent position is present in only one of the known Kir
subunits, the newly identified Kir1.3, which is also poorly expressed
in the recombinant system. When the lysine residue in guinea pig Kir1.3
(gpKir1.3) isolated from a genomic library was changed to an asparagine
(reverse HPS mutation), mutant channels yielded macroscopic currents
with amplitudes increased 6-fold. From single channel analysis it
became apparent that the decrease in mutant Kir1.1 channels and the
increase in mutant gpKir1.3 macroscopic currents were mainly due to the
number of expressed functional channels. Coexpression experiments
revealed a dominant-negative effect of Kir1.1a[N124K] and gpKir1.3 on
macroscopic current amplitudes when coexpressed with wild type Kir1.1a
and gpKir[K110N], respectively. Thus we postulate that in Kir1.3
channels the extracellular positively charged lysine is of crucial
functional importance. The HPS phenotype in man can be explained by the
lower expression of functional channels by the Kir1.1a[N124K]
mutant.
Institute for Physiology and
Department of Pediatrics, Philipps University, 35033 Marburg,
Germany and ¶ Molecular Neurobiology of Signal Transduction,
Max-Planck-Institute for Biophysical Chemistry,
37070 Göttingen, Germany
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