Characterization of a novel somatic KCNJ5 mutation delI157 in an aldosterone-producing adenoma

Meena Murthy, Azizan Elena Aisha, Morris J. Brown, Kevin M. O'Shaughnessy

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Objective: Adrenal aldosterone-producing adenomas (APAs) are an increasingly recognized cause of primary aldosteronism, and somatic mutations within the KCNJ5 gene encoding an inwardly rectifying K channel (also called GIRK4 or Kir3.4) have been identified by several groups including our own. We identified the previously noted G151R and L168R mutations in the region of a selectivity filter of the channel as well as a previously unreported 3-base deletion, delI157. Here, we report the functional properties of KCNJ5 channels carrying this novel delI157 mutation. Methods: The delI157 mutation was introduced into wild-type KCNJ5 sequences to allow its expression in both H295R cells and Xenopus oocytes to study its expression and electrophysiology, respectively. Results: In the adrenal cell line H295R, the delI157 mutant expresses and traffics normally to the cell surface. However, the current-voltage behavior of the mutant in oocytes is distinct from wild-type channels and mimics closely other selectivity filter mutations. In particular, its ability to support substantial current when extracellular K is replaced by Na. We also report for the first time that the mutants have reduced sensitivity to the KCNJ5 inhibitor tertiapin-Q that binds to the external vestibule of the channel pore. Conclusion: This novel KCNJ5 mutation behaves like the three selectivity filter mutations previously reported in APAs depolarizing the cell and showing reduced cation selectivity. The reduced sensitivity to tertiapin-Q suggests that the abnormal Na permeability of these selectivity mutations does indeed reflect structural changes around the mouth of the ion channel.

Original languageEnglish
Pages (from-to)1827-1833
Number of pages7
JournalJournal of Hypertension
Volume30
Issue number9
DOIs
Publication statusPublished - Sep 2012
Externally publishedYes

Fingerprint

Aldosterone
Adenoma
Mutation
Oocytes
Inwardly Rectifying Potassium Channel
Hyperaldosteronism
Aptitude
Electrophysiology
Xenopus
Ion Channels
Mouth
Cations
Permeability
Cell Line
Genes

Keywords

  • aldosterone-producing adenoma
  • hyperaldosteronism
  • hypertension
  • KCNJ5
  • potassium channels
  • selectivity filter
  • somatic mutation

ASJC Scopus subject areas

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Characterization of a novel somatic KCNJ5 mutation delI157 in an aldosterone-producing adenoma. / Murthy, Meena; Elena Aisha, Azizan; Brown, Morris J.; O'Shaughnessy, Kevin M.

In: Journal of Hypertension, Vol. 30, No. 9, 09.2012, p. 1827-1833.

Research output: Contribution to journalArticle

Murthy, Meena ; Elena Aisha, Azizan ; Brown, Morris J. ; O'Shaughnessy, Kevin M. / Characterization of a novel somatic KCNJ5 mutation delI157 in an aldosterone-producing adenoma. In: Journal of Hypertension. 2012 ; Vol. 30, No. 9. pp. 1827-1833.
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