PIP2 regulation of TRPC5 channel activation and desensitization

Abstract

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Nonselective TRPC channel inhibition and suppression of aminoglycoside-induced premature termination codon readthrough by the small molecule AC1903

“…Based on the findings described above, we wondered whether AC1903—which is typically used as a TRPC5 inhibitor at concentrations of 30–100 μM in cellular assays ( 29 , 56 )—might have limited selectivity for TRPC5 channels and whether its effect on intracellular G418 levels and PTC readthrough might be the consequence of inhibition of other or multiple targets. All well-characterized TRPC channel inhibitors reported to date modulate multiple TRP(C) channels ( 34 , 35 , 36 ).…”

“…As part of the development of AC1903, the compound was screened against a standard kinase panel, in which no off-target effects were found ( 29 ). In cellular experiments, AC1903 is typically used as a TRPC5 inhibitor at concentrations of 30 to 100 μM ( 29 , 56 ). However, our data suggest that TRPC3, TRPC4, TRPC6, and TRPV4 channels are important potential off-targets of AC1903 at these concentrations.…”

PKC regulation of ion channels: The involvement of PIP2

“…PIP 2 , phosphatidylinositol (4,5) bisphosphate.

Figure 3 PKC can regulate the activity of ion channels in a PIP 2 -dependent manner ( 31 , 39 , 57 , 58 , 63 , 95 , 173 ). Examples of ion channels where PKC regulation of their activity has been linked to alteration of channel–PIP 2 interactions.

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“…This residue is part of a VT 972 TRL motif, and it is likely that PKC phosphorylation at T972 may control the interaction of TRPC5 with PDZ domains of other proteins, such as Na + /H + exchanger regulatory factor (NHERF), precluding channel interactions with DAG ( 37 , 38 ). Using an elegant optogenetic tool to control rapid dephosphorylation of PIP 2 , it was recently shown that PKC-induced desensitization of TRPC5 through Thr972 is caused by weakening channel–PIP 2 interactions ( 39 ). In contrast, DAG enhanced channel–PIP 2 interactions and activated the channel ( 39 ).…”

“…Using an elegant optogenetic tool to control rapid dephosphorylation of PIP 2 , it was recently shown that PKC-induced desensitization of TRPC5 through Thr972 is caused by weakening channel–PIP 2 interactions ( 39 ). In contrast, DAG enhanced channel–PIP 2 interactions and activated the channel ( 39 ).…”