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Abstract
Na+–K+–2Cl− Cotransporter (NKCC1) is a protein that aids in the active transport of sodium, potassium, and chloride ions across cell membranes. It has been shown that long-term systemic treatment with aldosterone (ALD) can enhance NKCC1 protein expression and activity in the aging cochlea resulting in improved hearing. In the present work, we used a cell line with confirmed NKCC1 expression to demonstrate that in vitro application of ALD increased outward voltage-gated potassium currents significantly, and simultaneously upregulated whole lysate and membrane portion NKCC1 protein expression. These ALD-induced changes were blocked by applying the mineralocorticoid receptor antagonist eplerenone. However, application of the NKCC1 inhibitor bumetanide or the potassium channel antagonist Tetraethyl ammonium had no effect. In addition, NKKC1 mRNA levels remained stable, indicating that ALD modulates NKCC1 protein expression via the activation of mineralocorticoid receptors and post-transcriptional modifications. Further, in vitro electrophysiology experiments, with ALD in the presence of NKCC1, K+ channel and mineralocorticoid receptor inhibitors, revealed interactions between NKCC1 and outward K+ channels, mediated by a mineralocorticoid receptor-ALD complex. These results provide evidence of the therapeutic potential of ALD for the prevention/treatment of inner ear disorders such as age-related hearing loss.
Highlights
The increase in voltage-gated potassium currents following ALD application can be explain by NKCC1 upregulation in the cell membrane, mediated by mineralocorticoid receptors
The similarity between the results observed with BUM and TEA on inhibition of ALD induced voltage-gated K + currents suggests that the cross talk and interplay between NKCC1 and K + channels, and their mechanisms need further clarification
We have shown that long-term systemic treatment with ALD can prevent key aspects of ARHL in aging mice, indicating that ALD could potentially be a therapeutic agent for ARHL clinically[40]
Summary
Our goals were (1) Determine NKCC1 expression variants by stimulating SH-SY5Y neural cells with ALD and (2) Explore characteristics of NKCC1 functionality by recording voltagegated K+ outward currents driven by ALD
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