Human adrenal glomerulosa cells express K2P and GIRK potassium channels that are inhibited by ANG II and ACTH

Am J Physiol Cell Physiol. 2021 Jul 1;321(1):C158-C175. doi: 10.1152/ajpcell.00118.2021. Epub 2021 May 26.

Abstract

In whole cell patch clamp recordings, it was discovered that normal human adrenal zona glomerulosa (AZG) cells express members of the three major families of K+ channels. Among these are a two-pore (K2P) leak-type and a G protein-coupled, inwardly rectifying (GIRK) channel, both inhibited by peptide hormones that stimulate aldosterone secretion. The K2P current displayed properties identifying it as TREK-1 (KCNK2). This outwardly rectifying current was activated by arachidonic acid and inhibited by angiotensin II (ANG II), adrenocorticotrophic hormone (ACTH), and forskolin. The activation and inhibition of TREK-1 was coupled to AZG cell hyperpolarization and depolarization, respectively. A second K2P channel, TASK-1 (KCNK3), was expressed at a lower density in AZG cells. Human AZG cells also express inwardly rectifying K+ current(s) (KIR) that include quasi-instantaneous and time-dependent components. This is the first report demonstrating the presence of KIR in whole cell recordings from AZG cells of any species. The time-dependent current was selectively inhibited by ANG II, and ACTH, identifying it as a G protein-coupled (GIRK) channel, most likely KIR3.4 (KCNJ5). The quasi-instantaneous KIR current was not inhibited by ANG II or ACTH and may be a separate non-GIRK current. Finally, AZG cells express a voltage-gated, rapidly inactivating K+ current whose properties identified as KV1.4 (KCNA4), a conclusion confirmed by Northern blot. These findings demonstrate that human AZG cells express K2P and GIRK channels whose inhibition by ANG II and ACTH is likely coupled to depolarization-dependent secretion. They further demonstrate that human AZG K+ channels differ fundamentally from the widely adopted rodent models for human aldosterone secretion.

Keywords: ACTH; KCNJ5; TREK-1; angiotensin II; human adrenal glomerulosa.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adrenocorticotropic Hormone / pharmacology*
  • Adult
  • Aldosterone / biosynthesis
  • Angiotensin II / pharmacology*
  • Arachidonic Acid / pharmacology
  • Autopsy
  • Child
  • Colforsin / pharmacology
  • Female
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / genetics*
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • Gene Expression
  • Humans
  • Kv1.4 Potassium Channel / antagonists & inhibitors
  • Kv1.4 Potassium Channel / genetics*
  • Kv1.4 Potassium Channel / metabolism
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / physiology
  • Middle Aged
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Patch-Clamp Techniques
  • Potassium Channels, Tandem Pore Domain / antagonists & inhibitors
  • Potassium Channels, Tandem Pore Domain / genetics*
  • Potassium Channels, Tandem Pore Domain / metabolism
  • Primary Cell Culture
  • Zona Glomerulosa / cytology
  • Zona Glomerulosa / drug effects
  • Zona Glomerulosa / metabolism*

Substances

  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • KCNA4 protein, human
  • KCNJ5 protein, human
  • Kv1.4 Potassium Channel
  • Nerve Tissue Proteins
  • Potassium Channels, Tandem Pore Domain
  • potassium channel protein TREK-1
  • Angiotensin II
  • Colforsin
  • potassium channel subfamily K member 3
  • Arachidonic Acid
  • Aldosterone
  • Adrenocorticotropic Hormone