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Expression and Purification of the Human Lipid-sensitive Cation Channel TRPC3 for Structural Determination by Single-particle Cryo-electron Microscopy
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Inhibition of TRPC5 channels by intracellular ATP

Michael Dattilo1, Nicholas J Penington, Keith Williams

  • 1Department of Physiology and Pharmacology, Box 31, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, New York 11203, USA.

Molecular Pharmacology
|October 11, 2007
PubMed

Insights

TRPC5 channel activity, crucial for calcium signaling, is inhibited by intracellular ATP. This suggests TRPC5 channels may link cellular metabolism to calcium overload during conditions like ischemia when ATP levels drop.

Area of Science:

  • Ion channel physiology
  • Cellular signaling
  • G-protein coupled receptors

Background:

  • TRPC5 channels are calcium-permeable cation channels activated by G-protein coupled receptors.
  • The precise mechanisms of TRPC5 channel activation and regulation remain unclear.
  • Previous studies have yielded conflicting results regarding the role of intracellular nucleotides.

Purpose of the Study:

  • To investigate the role of intracellular nucleotides, specifically ATP, in the activation and regulation of TRPC5 channels.
  • To elucidate the signaling pathway involved in carbachol-induced TRPC5 currents.
  • To explore the potential link between TRPC5 channel activity, cellular metabolism, and ischemic conditions.

Main Methods:

  • Whole-cell patch clamp electrophysiology was used to record TRPC5 currents in human embryonic kidney 293 cells.
  • Cells were transiently transfected with TRPC5 and the M1 muscarinic receptor.
  • Intracellular perfusion systems were employed to control intracellular ATP levels and test nucleotide effects.

Main Results:

  • TRPC5 currents were robust in ATP- and GTP-free conditions, but absent or small when nucleotides were included in the pipette.
  • G-alpha(q) signaling pathway is essential for M1 receptor-mediated TRPC5 activation, as shown by inhibition with Pasteurella multocida toxin.
  • Intracellular perfusion of ATP or the non-hydrolyzable analog AMP-PNP significantly inhibited TRPC5 currents, indicating a direct, non-phosphorylative effect.

Conclusions:

  • TRPC5 channel activity is negatively regulated by intracellular ATP levels, suggesting a direct interaction with the channel.
  • The G-alpha(q) pathway mediates TRPC5 channel activation by M1 muscarinic receptors.
  • TRPC5 channel function may be modulated by cellular metabolic state, impacting calcium homeostasis, particularly during ischemic events.

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