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Gene Review

inaD  -  inactivation no afterpotential D

Drosophila melanogaster

Synonyms: CG3504, Dmel\CG3504, INAD, Ina-D, InaD, ...
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Disease relevance of inaD


High impact information on inaD

  • In Drosophila photoreceptors, the InaD protein, which consists of five PDZ domains, functions as a multivalent adaptor that brings together several components of the phototransduction cascade into a macromolecular complex [2].
  • Some of these proteins depend on INAD for proper subcellular localization to the phototransducing organelle, the rhabdomere, making it difficult to assess any physiological function of this signaling complex independent of localization [3].
  • Nevertheless, the INAD binding site was sufficient to target a heterologous protein to the rhabdomeres [3].
  • We show that in InaD mutant flies, TRP is no longer spatially restricted to its normal subcellular compartment, the rhabdomere [4].
  • InaD mutant flies have a M442K point mutation and display a slow recovery of the Ca2+ dependent current [5].

Chemical compound and disease context of inaD


Biological context of inaD


Anatomical context of inaD

  • We conclude that INAD acts as a scaffold protein that facilitates NORPA-TRP interactions required for gating of the TRP channel in photoreceptor cells [9].
  • At least seven proteins bind INAD, including the transient receptor potential (TRP) channel, which depends on INAD for localization to the phototransducing organelle, the rhabdomere [10].
  • As investigated by immunogold labeling with specific antibodies directed against Trp and InaD, the Trp signaling complex is located in the microvillar membranes of the photoreceptor cells [11].

Associations of inaD with chemical compounds

  • We report that anti-INAD antibodies coimmunoprecipitate TRP, identified by its electrophoretic mobility, cross reactivity with anti-TRP antibody, and absence in a null allele trp mutant [5].
  • In an approach directed to isolate and characterize key proteins of the transduction cascade in photoreceptors using the phosphoinositide signaling pathway, we have isolated the Calliphora homolog of the Drosophila InaD gene product, which in Drosophila InaD mutants causes slow deactivation of the light response [12].
  • Light-activated Galpha(q)- guanosine 5'-O-(thiotriphosphate) and AlF(4)(-)-activated Galpha(q), but not Gbetagamma, form a stable complex with the INAD signaling complex [13].
  • Thus the coupling between the depletion of Ca(2+) stores and the activation of CRAC channels may involve a mammalian homologue of INAD and a low-molecular-weight, diffusible store-depletion signal [14].

Physical interactions of inaD

  • Inactivation-no-afterpotential D (INAD) is an adaptor protein containing PDZ domains known to interact with TRP [9].
  • We previously showed that eye-PKC interacted with the second PDZ domain (PDZ2) of INAD [15].
  • We have determined the crystal structure of the N-terminal PDZ domain of InaD bound to a peptide corresponding to the C-terminus of NorpA to 1.8 A resolution [16].

Regulatory relationships of inaD

  • In the present study we show that the Calliphora rpa mutant, which has previously been hypothesized to represent an equivalent of Drosophila norpA mutants, has normal amounts of norpA mRNA but fails to express inaD mRNA [17].
  • These results suggest that the INAD macromolecular complex plays an essential role in termination of the light response by promoting efficient phosphorylation at Ser982 of TRP for fast deactivation of the visual signaling [18].

Other interactions of inaD

  • Two distantly positioned PDZ domains mediate multivalent INAD-phospholipase C interactions essential for G protein-coupled signaling [7].
  • To identify substrates of eye-PKC, we immunoprecipitated the complex from head lysates using anti-INAD antibodies and performed in vitro kinase assays [8].
  • These results provide strong support for the hypothesis that immunophilin dFKBP59 is part of the TRPL-INAD signaling complex and plays an important role in modulation of channel activity via interaction with conserved leucyl-prolyl dipeptides located near the cytoplasmic mouth of the channel [19].
  • Likewise, INAD immunoprecipitates with dFKBP59 from S2 cell and head lysates [19].
  • Functional INAD complexes are required to mediate degeneration in photoreceptors of the Drosophila rdgA mutant [1].

Analytical, diagnostic and therapeutic context of inaD

  • By overlay assay and site-directed mutagenesis we have defined the essential elements of the NORPA-INAD association and identified three critical residues in the C-terminal tail of NORPA that are required for the interaction [9].
  • We have used immunoprecipitation assays to study the interaction of the heterotrimeric visual G protein with this INAD signaling complex [13].


  1. Functional INAD complexes are required to mediate degeneration in photoreceptors of the Drosophila rdgA mutant. Georgiev, P., Garcia-Murillas, I., Ulahannan, D., Hardie, R.C., Raghu, P. J. Cell. Sci. (2005) [Pubmed]
  2. Assembly of the Drosophila phototransduction cascade into a signalling complex shapes elementary responses. Scott, K., Zuker, C.S. Nature (1998) [Pubmed]
  3. Termination of phototransduction requires binding of the NINAC myosin III and the PDZ protein INAD. Wes, P.D., Xu, X.Z., Li, H.S., Chien, F., Doberstein, S.K., Montell, C. Nat. Neurosci. (1999) [Pubmed]
  4. Requirement for the PDZ domain protein, INAD, for localization of the TRP store-operated channel to a signaling complex. Chevesich, J., Kreuz, A.J., Montell, C. Neuron (1997) [Pubmed]
  5. Regulation of the TRP Ca2+ channel by INAD in Drosophila photoreceptors. Shieh, B.H., Zhu, M.Y. Neuron (1996) [Pubmed]
  6. Dissecting independent channel and scaffolding roles of the Drosophila transient receptor potential channel. Wang, T., Jiao, Y., Montell, C. J. Cell Biol. (2005) [Pubmed]
  7. Two distantly positioned PDZ domains mediate multivalent INAD-phospholipase C interactions essential for G protein-coupled signaling. van Huizen, R., Miller, K., Chen, D.M., Li, Y., Lai, Z.C., Raab, R.W., Stark, W.S., Shortridge, R.D., Li, M. EMBO J. (1998) [Pubmed]
  8. Reversible phosphorylation of the signal transduction complex in Drosophila photoreceptors. Liu, M., Parker, L.L., Wadzinski, B.E., Shieh, B.H. J. Biol. Chem. (2000) [Pubmed]
  9. Association of INAD with NORPA is essential for controlled activation and deactivation of Drosophila phototransduction in vivo. Shieh, B.H., Zhu, M.Y., Lee, J.K., Kelly, I.M., Bahiraei, F. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  10. TRP and the PDZ protein, INAD, form the core complex required for retention of the signalplex in Drosophila photoreceptor cells. Li, H.S., Montell, C. J. Cell Biol. (2000) [Pubmed]
  11. The transient receptor potential protein (Trp), a putative store-operated Ca2+ channel essential for phosphoinositide-mediated photoreception, forms a signaling complex with NorpA, InaC and InaD. Huber, A., Sander, P., Gobert, A., Bähner, M., Hermann, R., Paulsen, R. EMBO J. (1996) [Pubmed]
  12. Phosphorylation of the InaD gene product, a photoreceptor membrane protein required for recovery of visual excitation. Huber, A., Sander, P., Paulsen, R. J. Biol. Chem. (1996) [Pubmed]
  13. The visual G protein of fly photoreceptors interacts with the PDZ domain assembled INAD signaling complex via direct binding of activated Galpha(q) to phospholipase cbeta. Bähner, M., Sander, P., Paulsen, R., Huber, A. J. Biol. Chem. (2000) [Pubmed]
  14. Regulation of Ca2+ release-activated Ca2+ channels by INAD and Ca2+ influx factor. Su, Z., Barker, D.S., Csutora, P., Chang, T., Shoemaker, R.L., Marchase, R.B., Blalock, J.E. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  15. The second PDZ domain of INAD is a type I domain involved in binding to eye protein kinase C. Mutational analysis and naturally occurring variants. Kumar, R., Shieh, B.H. J. Biol. Chem. (2001) [Pubmed]
  16. Functional relevance of the disulfide-linked complex of the N-terminal PDZ domain of InaD with NorpA. Kimple, M.E., Siderovski, D.P., Sondek, J. EMBO J. (2001) [Pubmed]
  17. The Calliphora rpa mutant lacks the PDZ domain-assembled INAD signalling complex. Huber, A., Belusic, G., Da Silva, N., Bähner, M., Gerdon, G., Draslar, K., Paulsen, R. Eur. J. Neurosci. (2000) [Pubmed]
  18. Scaffolding protein INAD regulates deactivation of vision by promoting phosphorylation of transient receptor potential by eye protein kinase C in Drosophila. Popescu, D.C., Ham, A.J., Shieh, B.H. J. Neurosci. (2006) [Pubmed]
  19. Regulation of Drosophila TRPL channels by immunophilin FKBP59. Goel, M., Garcia, R., Estacion, M., Schilling, W.P. J. Biol. Chem. (2001) [Pubmed]
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