Faculty Collaboration Database

Crosstalk between epithelial sodium channels (ENaC) and basolateral potassium channels (K_ir 4.1/K_ir 5.1) in the cortical collecting duct. Br J Pharmacol 2022 Jun;179(12):2953-2968

Date

12/15/2021

Pubmed ID

34904226

Pubmed Central ID

PMC9106811

DOI

10.1111/bph.15779

Scopus ID

2-s2.0-85124542688 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

BACKGROUND AND PURPOSE: Inwardly rectifying K⁺ (K_ir ) channels located on the basolateral membrane of epithelial cells of the distal nephron play a crucial role in K⁺ handling and BP control, making these channels an attractive target for the treatment of hypertension. The purpose of the present study was to determine how the inhibition of basolateral K_ir 4.1/K_ir 5.1 heteromeric K⁺ channel affects epithelial sodium channel (ENaC)-mediated Na⁺ transport in the principal cells of cortical collecting duct (CCD).

EXPERIMENTAL APPROACH: The effect of fluoxetine, amitriptyline and recently developed K_ir inhibitor, VU0134992, on the activity of K_ir 4.1, K_ir 4.1/K_ir 5.1 and ENaC were tested using electrophysiological approaches in CHO cells transfected with respective channel subunits, cultured polarized epithelial mCCD_cl1 cells and freshly isolated rat and human CCD tubules. To test the effect of pharmacological K_ir 4.1/K_ir 5.1 inhibition on electrolyte homeostasis in vivo and corresponding changes in distal tubule transport, Dahl salt-sensitive rats were injected with amitriptyline (15 mg·kg^-1 ·day^-1 ) for 3 days.

KEY RESULTS: We found that inhibition of K_ir 4.1/K_ir 5.1, but not the K_ir 4.1 channel, depolarizes the cell membrane, induces the elevation of intracellular Ca²⁺ concentration and suppresses ENaC activity. Furthermore, we demonstrate that amitriptyline administration leads to a significant drop in plasma K⁺ level, triggering sodium excretion and diuresis.

CONCLUSION AND IMPLICATIONS: The present data uncover a specific role of the K_ir 4.1/K_ir 5.1 channel in the modulation of ENaC activity and emphasize the potential for using K_ir 4.1/K_ir 5.1 inhibitors to regulate electrolyte homeostasis and BP.

Author List

Isaeva E, Bohovyk R, Fedoriuk M, Shalygin A, Klemens CA, Zietara A, Levchenko V, Denton JS, Staruschenko A, Palygin O

Author

Olena Isaeva PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Amitriptyline
Animals
Cricetinae
Cricetulus
Electrolytes
Epithelial Sodium Channels
Kidney Tubules, Collecting
Potassium Channels, Inwardly Rectifying
Rats
Rats, Inbred Dahl
Sodium