Phospholipase Cγ1 controls surface expression of TRPC3 through an intermolecular PH domain


Many ion channels are regulated by lipids1,2,3, but prominent motifs for lipid binding have not been identified in most ion channels. Recently, we reported that phospholipase Cγ1 (PLC-γ1) binds to and regulates TRPC3 channels4, components of agonist-induced Ca2+ entry into cells. This interaction requires a domain in PLC-γ1 that includes a partial pleckstrin homology (PH) domain—a consensus lipid-binding and protein-binding sequence5,6. We have developed a gestalt algorithm to detect hitherto ‘invisible’ PH and PH-like domains, and now report that the partial PH domain of PLC-γ1 interacts with a complementary partial PH-like domain in TRPC3 to elicit lipid binding and cell-surface expression of TRPC3. Our findings imply a far greater abundance of PH domains than previously appreciated, and suggest that intermolecular PH-like domains represent a widespread signalling mode.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: The PLC-γ1 PH-c domain binds directly to amino acids 40–46 in TRPC3.
Figure 2: TRPC3 possesses an invisible PH-n domain at the site of PLC-γ1 PH-c binding.
Figure 3: Interaction between PLC-γ1 PH-c and TRPC3 confers lipid binding and affects membrane expression.
Figure 4: Intermolecular PH-like domain formation controls the surface expression of TRPC3.


  1. 1

    Runnels, L. W., Yue, L. & Clapham, D. E. The TRPM7 channel is inactivated by PIP(2) hydrolysis. Nature Cell Biol. 4, 329–336 (2002)

  2. 2

    Prescott, E. D. & Julius, D. A modular PIP2 binding site as a determinant of capsaicin receptor sensitivity. Science 300, 1284–1288 (2003)

  3. 3

    Suh, B. C. & Hille, B. Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis. Neuron 35, 507–520 (2002)

  4. 4

    Patterson, R. L. et al. Phospholipase C-γ is required for agonist-induced Ca2+ entry. Cell 111, 529–541 (2002)

  5. 5

    DiNitto, J. P., Cronin, T. C. & Lambright, D.G. Membrane recognition and targeting by lipid-binding domains. Sci. STKE. re16 (2003).

  6. 6

    Rebecchi, M. J. & Scarlata, S. Pleckstrin homology domains: a common fold with diverse functions. Annu. Rev. Biophys. Biomol. Struct. 27, 503–528 (1998)

  7. 7

    Marchler-Bauer, A. et al. CDD: a curated Entrez database of conserved domain alignments. Nucleic Acids Res. 31, 383–387 (2003)

  8. 8

    Bateman, A. et al. The Pfam protein families database. Nucleic Acids Res. 32, D138–D141 (2004)

  9. 9

    Gattiker, A., Gasteiger, E. & Bairoch, A. ScanProsite: a reference implementation of a PROSITE scanning tool. Appl. Bioinform. 1, 107–108 (2002)

  10. 10

    Letunic, I. et al. SMART 4.0: towards genomic data integration. Nucleic Acids Res. 32, D142–D144 (2004)

  11. 11

    Jogl, G. et al. Crystal structure of the BEACH domain reveals an unusual fold and extensive association with a novel PH domain. EMBO J. 21, 4785–4795 (2002)

  12. 12

    Gervais, V. et al. TFIIH contains a PH domain involved in DNA nucleotide excision repair. Nature Struct. Mol. Biol. 11, 616–622 (2004)

  13. 13

    Vetter, I. R., Nowak, C., Nishimoto, T., Kuhlmann, J. & Wittinghofer, A. Structure of a Ran-binding domain complexed with Ran bound to a GTP analogue: implications for nuclear transport. Nature 398, 39–46 (1999)

  14. 14

    Ma, H. T. et al. Requirement of the inositol trisphosphate receptor for activation of store-operated Ca2+ channels. Science 287, 1647–1651 (2000)

  15. 15

    Baranano, D. E. et al. A mammalian iron ATPase induced by iron. J. Biol. Chem. 275, 15166–15173 (2000)

Download references


We thank D. Boehning, G. Caraveo, J. Kendall, A. Resnick and R. E. Rothe for discussion; P.-G. Suh for the gift of the PLC-γ1 antibody; and B. VanRossum for graphics. This research was supported by US Public Health Service Grants and a Research Scientist Award (to S.H.S.), a National Institutes of Health Grant (to D.L.G.), and National Research Service Awards (to R.L.P.).

Author information



Corresponding author

Correspondence to Solomon H. Snyder.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figures 1-3

Complementation analyses identify PH domain code within TRPC3, smallwing, alpha 1 syntrophin, syngap and TRPV1. (PDF 447 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

van Rossum, D., Patterson, R., Sharma, S. et al. Phospholipase Cγ1 controls surface expression of TRPC3 through an intermolecular PH domain. Nature 434, 99–104 (2005).

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.