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.
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| http://dx.doi.org/10.1038/s41598-020-72450-4 | DOI Listing |
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Article Synopsis
- KCC2 is a cotransporter in neurons that regulates chloride levels, crucial for the function of inhibitory neurotransmitters like GABA and glycine; low KCC2 levels can lead to increased neuronal excitability associated with disorders like epilepsy and neuropathic pain.
- Axotomy (nerve injury) reduces KCC2 levels in motoneurons, but if the muscle reinnervation occurs, KCC2 levels can recover, suggesting the influence of neurotrophic factors.
- Administration of VEGF can prevent the KCC2 downregulation after axotomy, while BDNF may decrease KCC2 levels, indicating potential therapeutic avenues for conditions linked to neuronal hyperactivity.
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