Mammalian members of the classical transient receptor potential channel subfamily (TRPC) are Ca(2+)-permeable cation channels involved in receptor-mediated increases in intracellular Ca(2+). TRPC4 and TRPC5 form a group within the TRPC subfamily and are activated in a phospholipase C-dependent manner by an unidentified messenger. Unlike most other Ca(2+)-permeable channels, TRPC4 and -5 are potentiated by micromolar concentrations of La(3+) and Gd(3+). This effect results from an action of the cations at two glutamate residues accessible from the extracellular solution. Here, we show that TRPC4 and -5 respond to changes in extracellular pH. Lowering the pH increased both G protein-activated and spontaneous TRPC5 currents. Both effects were already observed with small reductions in pH (from 7.4 to 7.0) and increased up to pH 6.5. TRPC4 was also potentiated by decreases in pH, whereas TRPC6 was only inhibited, with a pIC(50) of 5.7. Mutation of the glutamate residues responsible for lanthanoid sensitivity of TRPC5 (E543Q and E595Q) modified the potentiation of TRPC5 by acid. Further evidence for a similarity in the actions of lanthanoids and H(+) on TRPC5 is the reduction in single channel conductance and dramatic increase in channel open probability in the presence of either H(+) or Gd(3+) that leads to larger integral currents. In conclusion, the high sensitivity of TRPC5 to H(+) indicates that, in addition to regulation by phospholipase C and other factors, the channel may act as a sensor of pH that links decreases in extracellular pH to Ca(2+) entry and depolarization.