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Serine 232 of the alpha(2A)-adrenergic receptor is a protein kinase C-sensitive effector coupling switch.

Publication ,  Journal Article
Liang, M; Freedman, NJ; Theiss, CT; Liggett, SB
Published in: Biochemistry
December 11, 2001

alpha(2)-adrenergic receptors (alpha(2)AR) couple to multiple effectors including adenylyl cyclase and phospholipase C. We hypothesized that signaling selectivity to these effectors is dynamically directed by kinase-sensitive domains within the third intracellular loop of the receptor. Substitution of Ala for Ser232, which is in the N-terminal region of this loop in the alpha(2A)AR, resulted in a receptor that was markedly uncoupled ( approximately 82% impairment) from stimulation of inositol phosphate accumulation while the capacity to inhibit adenylyl cyclase remained relatively intact. In S232A alpha(2A)AR transfected cell membranes, agonist-promoted [(35)S]GTPgammaS binding was reduced by approximately 50%. Coexpression of modified G proteins rendered insensitive to pertussis toxin revealed that the S232A receptor was uncoupled from both G(i) and G(o). S232 is a potential PKC phosphorylation site, and whole cell phosphorylation studies showed that the mutant had depressed phosphorylation compared to wild type (1.3- vs 2.1-fold/basal). Consistent with S232 directing coupling to phospholipase C, PMA exposure resulted in approximately 67% desensitization of agonist-promoted inositol phosphate accumulation without significantly affecting inhibition of adenylyl cyclase. The dominant effect of mutation or phosphorylation at this site on inositol phosphate as compared to cAMP signaling was found to most likely be due to the low efficiency of signal transduction via phospholipase C vs adenylyl cyclase. Taken together, these results indicate that S232 acts as a selective, PKC-sensitive, modulator of effector coupling of the alpha(2A)AR to inositol phosphate stimulation. This represents one mechanism by which cells route stimuli directed to multifunctional receptors to selected effectors so as to attain finely targeted signaling.

Duke Scholars

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

December 11, 2001

Volume

40

Issue

49

Start / End Page

15031 / 15037

Location

United States

Related Subject Headings

  • Virulence Factors, Bordetella
  • Thrombin
  • Signal Transduction
  • Sequence Alignment
  • Receptors, Adrenergic, alpha-2
  • Protein Kinase C
  • Phosphorylation
  • Pertussis Toxin
  • Mutagenesis, Site-Directed
  • Molecular Sequence Data
 

Citation

APA
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MLA
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Liang, M., Freedman, N. J., Theiss, C. T., & Liggett, S. B. (2001). Serine 232 of the alpha(2A)-adrenergic receptor is a protein kinase C-sensitive effector coupling switch. Biochemistry, 40(49), 15031–15037. https://doi.org/10.1021/bi011453z
Liang, M., N. J. Freedman, C. T. Theiss, and S. B. Liggett. “Serine 232 of the alpha(2A)-adrenergic receptor is a protein kinase C-sensitive effector coupling switch.Biochemistry 40, no. 49 (December 11, 2001): 15031–37. https://doi.org/10.1021/bi011453z.
Liang M, Freedman NJ, Theiss CT, Liggett SB. Serine 232 of the alpha(2A)-adrenergic receptor is a protein kinase C-sensitive effector coupling switch. Biochemistry. 2001 Dec 11;40(49):15031–7.
Liang, M., et al. “Serine 232 of the alpha(2A)-adrenergic receptor is a protein kinase C-sensitive effector coupling switch.Biochemistry, vol. 40, no. 49, Dec. 2001, pp. 15031–37. Pubmed, doi:10.1021/bi011453z.
Liang M, Freedman NJ, Theiss CT, Liggett SB. Serine 232 of the alpha(2A)-adrenergic receptor is a protein kinase C-sensitive effector coupling switch. Biochemistry. 2001 Dec 11;40(49):15031–15037.
Journal cover image

Published In

Biochemistry

DOI

ISSN

0006-2960

Publication Date

December 11, 2001

Volume

40

Issue

49

Start / End Page

15031 / 15037

Location

United States

Related Subject Headings

  • Virulence Factors, Bordetella
  • Thrombin
  • Signal Transduction
  • Sequence Alignment
  • Receptors, Adrenergic, alpha-2
  • Protein Kinase C
  • Phosphorylation
  • Pertussis Toxin
  • Mutagenesis, Site-Directed
  • Molecular Sequence Data