Potentiation of TRPC5 by protons

Area of Science:

• Physiology
• Molecular Biology
• Biophysics

Background:

• Mammalian classical transient receptor potential (TRPC) channels are Ca(2+)-permeable cation channels.
• TRPC4 and TRPC5 form a distinct group within the TRPC subfamily, activated by phospholipase C.
• These channels are uniquely potentiated by lanthanides like La(3+) and Gd(3+) acting on extracellular glutamate residues.

Purpose of the Study:

• To investigate the effect of extracellular pH on TRPC4 and TRPC5 channel activity.
• To determine if pH influences TRPC channel function similarly to lanthanides.
• To explore the potential role of TRPC5 as a pH sensor.

Main Methods:

• Electrophysiological recordings of TRPC4, TRPC5, and TRPC6 currents.
• Utilized mutations (E543Q and E595Q) in TRPC5 to assess the role of specific glutamate residues.
• Manipulated extracellular pH levels and measured changes in channel activity.

Main Results:

• Decreasing extracellular pH potentiated both G protein-activated and spontaneous TRPC5 currents, with effects observed at pH 7.0 and increasing down to pH 6.5.
• TRPC4 activity was also potentiated by decreased pH, while TRPC6 was inhibited (pIC(50) = 5.7).
• Mutating glutamate residues (E543Q, E595Q) in TRPC5 altered its potentiation by acid, mirroring lanthanide effects, including reduced single channel conductance and increased open probability.

Conclusions:

• TRPC4 and TRPC5 channels exhibit significant sensitivity to extracellular pH changes.
• The potentiation of TRPC5 by H+ ions shares similarities with lanthanide potentiation, involving specific glutamate residues.
• TRPC5 may function as a physiological pH sensor, linking extracellular pH fluctuations to Ca(2+) influx and cell depolarization.