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Phosducin, potential role in modulation of olfactory signaling.

Publication ,  Journal Article
Boekhoff, I; Touhara, K; Danner, S; Inglese, J; Lohse, MJ; Breer, H; Lefkowitz, RJ
Published in: J Biol Chem
February 14, 1997

Phosducin, which tightly binds betagamma-subunits of heterotrimeric G-proteins, has been conjectured to play a role in regulating second messenger signaling cascades, but to date its specific function has not been elucidated. Here we demonstrate a potential role for phosducin in regulating olfactory signal transduction. In isolated olfactory cilia certain odorants elicit a rapid and transient cAMP response, terminated by a concerted process which requires the action of two protein kinases, protein kinase A (PKA) and a receptor-specific kinase (GRK3) (Schleicher, S., Boekhoff, I. Arriza, J., Lefkowitz, R. J., and Breer, H. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 1420-1424). The mechanism of action of GRK3 involves a Gbetagamma-mediated translocation of the kinase to the plasma membrane bound receptors (Pitcher, J. A., Inglese, J., Higgins, J. B. , Arriza, J. L., Casey, P. J., Kim, C., Benovic, J. L., Kwatra, M. M. , Caron, M. G., and Lefkowitz, R. J. (1992) Science 257, 1264-1267). A protein with a molecular mass of 33 kDa that comigrates on SDS gels with recombinant phosducin and which is immunoreactive with phosducin antibodies is present in olfactory cilia. Recombinant phosducin added to permeabilized olfactory cilia preparations strongly inhibits termination of odorant-induced cAMP response and odorant-induced membrane translocation of GRK3. In addition, the cAMP analogue dibutyryl cAMP stimulates membrane targeting of the receptor kinase. This effect is presumably due to PKA-mediated phosphorylation of phosducin, which diminishes its affinity for binding to the Gbetagamma-subunit, thereby making Gbetagamma available to function as a membrane anchor for GRK3. A specific PKA inhibitor blocks the odorant-induced translocation of the receptor kinase. Consistent with this formulation, a non-phosphorylatable mutant of phosducin (phosducin Ser-73 --> Ala) is an even more effective inhibitor of desensitization and membrane targeting of GRK3 than the wild-type protein. A phosducin mutant that mimics phosphorylated phosducin (phosducin Ser-73 --> Asp) lacks this property and in fact recruits GRK3 to the membrane and potentiates desensitization. These results suggest that phosducin may act as a phosphorylation-dependent switch in second messenger signaling cascades, regulating the kinetics of desensitization processes by controlling the activity of Gbetagamma-dependent GRKs.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

February 14, 1997

Volume

272

Issue

7

Start / End Page

4606 / 4612

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptor Protein-Tyrosine Kinases
  • Rats, Sprague-Dawley
  • Rats
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Phosphoproteins
  • Olfactory Pathways
  • Mutagenesis, Site-Directed
  • Membrane Proteins
 

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Boekhoff, I., Touhara, K., Danner, S., Inglese, J., Lohse, M. J., Breer, H., & Lefkowitz, R. J. (1997). Phosducin, potential role in modulation of olfactory signaling. J Biol Chem, 272(7), 4606–4612. https://doi.org/10.1074/jbc.272.7.4606
Boekhoff, I., K. Touhara, S. Danner, J. Inglese, M. J. Lohse, H. Breer, and R. J. Lefkowitz. “Phosducin, potential role in modulation of olfactory signaling.J Biol Chem 272, no. 7 (February 14, 1997): 4606–12. https://doi.org/10.1074/jbc.272.7.4606.
Boekhoff I, Touhara K, Danner S, Inglese J, Lohse MJ, Breer H, et al. Phosducin, potential role in modulation of olfactory signaling. J Biol Chem. 1997 Feb 14;272(7):4606–12.
Boekhoff, I., et al. “Phosducin, potential role in modulation of olfactory signaling.J Biol Chem, vol. 272, no. 7, Feb. 1997, pp. 4606–12. Pubmed, doi:10.1074/jbc.272.7.4606.
Boekhoff I, Touhara K, Danner S, Inglese J, Lohse MJ, Breer H, Lefkowitz RJ. Phosducin, potential role in modulation of olfactory signaling. J Biol Chem. 1997 Feb 14;272(7):4606–4612.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

February 14, 1997

Volume

272

Issue

7

Start / End Page

4606 / 4612

Location

United States

Related Subject Headings

  • Signal Transduction
  • Receptor Protein-Tyrosine Kinases
  • Rats, Sprague-Dawley
  • Rats
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Phosphoproteins
  • Olfactory Pathways
  • Mutagenesis, Site-Directed
  • Membrane Proteins