Ion channels regulate energy homeostasis and the progression of metabolic disorders: Novel mechanisms and pharmacology of their modulators.

The progression of metabolic diseases, featured by dysregulated metabolic signaling pathways, is orchestrated by numerous signaling networks. Among the regulators, ion channels transport ions across the membranes and trigger downstream signaling transduction. They critically regulate energy homeostasis and pathogenesis of metabolic diseases and are potential therapeutic targets for treating metabolic disorders. Ion channel blockers have been used to treat diabetes for decades by stimulating insulin secretion, yet with hypoglycemia and other adverse effects. It calls for deeper understanding of the largely elusive regulatory mechanisms, which facilitates the identification of new therapeutic targets and safe drugs against ion channels. In the article, we critically assess the two principal regulatory mechanisms, protein-channel interaction and post-translational modification on the activities of ion channels to modulate energy homeostasis and metabolic disorders through multiple novel mechanisms. Moreover, we discuss the multidisciplinary methods that provide the tools for elucidation of the regulatory mechanisms mediating metabolic disorders by ion channels. In terms of translational perspective, the mechanistic analysis of recently validated ion channels that regulate insulin resistance, body weight control, and adverse effects of current ion channel antagonists are discussed in details. Their small molecule modulators serve as promising new drug candidates to combat metabolic disorders.