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Opening doors to drug discovery: Insights into the inhibition of ion channels

Researchers have found how drug-like small molecules can regulate the activity of therapeutically relevant ion channels – findings which could transform ongoing drug development efforts.


Transient Receptor Potential Canonical (TRPC) proteins form homo- or heterotetrameric, non-selective cation channels permeable by calcium and sodium. The mammalian TRPC protein can be divided into sub-groups: TRPC1/4/5, TRPC3/6/7 and TRPC2. TRPC1/4/5 channels have been implicated in a wide range of physiological and pathological mechanisms. These findings have driven the development of potent and selective modulators of these channels as chemical probes and drug candidates. Current clinical trials of these modulators are underway.

The physiological activation and modulation of TRPC1/4/5 channel activity is complex. It can be mediated by endogenous and dietary lipids and metal ions (e.g. zinc). Structurally diverse pharmacological modulators have also been reported. These include inhibitors such as xanthines Pico145 (which are the most potent and selective). Nonetheless, structural insights into the mode-of-action of small-molecule TRPC1/4/5 modulators is lacking. Moreover, researchers have yet to identify small-molecule-binding sites.

Figure: Structure of human TRPC5 in complex with Pico145

Regulation of ion channels

In this study, published in Communications Biology, researchers reported the structure of the TRPC5 channels in complex with the xanthine Pico145 using cryo-electron microscopy. They found that Pico145 binds to a conserved lipid binding site of TRPC5 where it displaces a bound phospholipid. Further studies also revealed the importance of individual amino acid residues in the Pico145 binding site of TRPC5. These findings explain the mode-of-action of xanthine-based TRPC1/4/5 modulators.

Many diseases are linked to defects in ion channel function. As a result, controlling the opening and closing of specific ion channels is a highly successful therapeutic strategy. TRPC5 channels are considered potential therapeutic targets for the treatment of a range of conditions, including anxiety, kidney disease and cardiovascular disease. However, drug discovery efforts are often hindered by limited understanding of how drug-like small molecules can be designed to control ion channel activity. These findings represent a breakthrough that may provide new, rational approaches to the development of drug candidates that target TRPC channels.

Image credit: By cdascher –

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