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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
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Discovery and characterization of a positive allosteric modulator of transient receptor potential canonical 6 (TRPC6)

S Häfner1, N Urban1, M Schaefer1

  • 1Rudolf-Boehm-Institute of Pharmacology and Toxicology, Medical Faculty, Leipzig University, Härtelstraße 16-18, 04107 Leipzig, Germany.

Cell Calcium
|December 30, 2018
PubMed

Insights

A novel compound, C20, selectively enhances TRPC6 channel activity by acting as an allosteric modulator. This discovery offers a new tool for studying TRPC6-dependent signaling pathways and developing targeted therapies.

Area of Science:

  • Ion channel pharmacology
  • Molecular and cellular biology
  • Drug discovery

Background:

  • Transient receptor potential canonical 6 (TRPC6) channels are crucial ion channels involved in various physiological and pathological processes.
  • Developing selective modulators for TRPC6 is essential for understanding its function and for therapeutic interventions.
  • Existing activators like OAG lack selectivity and can activate other TRPC channels and pathways.

Purpose of the Study:

  • To identify and characterize novel small molecules that modulate TRPC6 channel activity.
  • To investigate the mechanism of action of a newly identified TRPC6 modulator.
  • To evaluate the utility of the compound in native systems like human platelets.

Main Methods:

  • High-throughput screening of a chemical library to identify TRPC6 modulators.
  • Calcium imaging assays (Ca2+ assays) to measure intracellular calcium levels.
  • Electrophysiological studies to assess channel function.
  • Synthesis of the identified compound (C20) using a one-pot strategy.

Main Results:

  • A novel compound, C20, was identified that selectively enhances TRPC6 channel activity with an EC50 of 2.37 μM.
  • C20 acts as an allosteric modulator, sensitizing TRPC6 to low concentrations of diacylglycerols (DAG) rather than directly activating it.
  • C20 potentiated TRPC6-mediated calcium influx in human platelets when combined with OAG, demonstrating its efficacy in a native system.
  • The compound's effects were confirmed to be TRPC6-specific and sensitive to TRPC6 blockers.

Conclusions:

  • C20 is a valuable pharmacological tool that selectively enhances TRPC6 channel activation.
  • Its allosteric modulatory mechanism provides a novel approach to targeting TRPC6.
  • C20 holds promise for further research into TRPC6-dependent signaling and the development of new therapeutic strategies.
Keywords:
Calcium ion influxCompound library screeningPatch clamp electrophysiologyPlateletsPositive allosteric modulatorTransient receptor potential channel

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