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Molecular Pharmacology

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Research ArticleArticle

Enhanced Hypotensive, Bradycardic, and Hypnotic Responses to α2-Adrenergic Agonists in Spinophilin-Null Mice Are Accompanied by Increased G Protein Coupling to the α2A-Adrenergic Receptor

R. Lu, Y. Chen, C. Cottingham, N. Peng, K. Jiao, L. E. Limbird, J. M. Wyss and Q. Wang
Molecular Pharmacology August 2010, 78 (2) 279-286; DOI: https://doi.org/10.1124/mol.110.065300
R. Lu
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Y. Chen
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C. Cottingham
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N. Peng
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K. Jiao
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L. E. Limbird
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J. M. Wyss
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Q. Wang
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Abstract

We previously identified spinophilin as a regulator of α2 adrenergic receptor (α2AR) trafficking and signaling in vitro and in vivo (Science 304:1940–1944, 2004). To assess the generalized role of spinophilin in regulating α2AR functions in vivo, the present study examined the impact of eliminating spinophilin on α2AR-evoked cardiovascular and hypnotic responses, previously demonstrated to be mediated by the α2AAR subtype, after systemic administration of the α2-agonists 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK14,304) and clonidine in spinophilin-null mice. Mice lacking spinophilin expression display dramatically enhanced and prolonged hypotensive, bradycardic, and sedative-hypnotic responses to α2AR stimulation. Whereas these changes in sensitivity to α2AR agonists occur independent of any changes in α2AAR density or intrinsic affinity for agonist in the brains of spinophilin-null mice compared with wild-type control mice, the coupling of the α2AAR to cognate G proteins is enhanced in spinophilin-null mice. Thus, brain preparations from spinophilin-null mice demonstrate enhanced guanine nucleotide regulation of UK14,304 binding and evidence of a larger fraction of α2AAR in the guanine-nucleotide-sensitive higher affinity state compared with those from wild-type mice. These findings suggest that eliminating spinophilin expression in native tissues leads to an enhanced receptor/G protein coupling efficiency that contributes to sensitization of receptor mediated responses in vivo.

Footnotes

  • This work was supported in part by the National Institutes of Health National Institute of Mental Health [Grant MH081917], by the American Heart Association [Grant 0630103N], and by the UAB Neuroscience Core Centers (funded by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grants NS047466, NS057098]). Preliminary studies were funded by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK43879].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.065300.

  • ABBREVIATIONS:

    AR
    α2-adrenergic receptor
    GPCR
    G protein-coupled receptor
    UK14
    304, 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine
    WT
    wild type
    LORR
    loss of righting reflex
    Gpp(NH)p
    5′-guanylimidodiphosphate.

  • Received April 2, 2010.
  • Accepted April 29, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (2)
Molecular Pharmacology
Vol. 78, Issue 2
1 Aug 2010
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Research ArticleArticle

Enhanced Hypotensive, Bradycardic, and Hypnotic Responses to α2-Adrenergic Agonists in Spinophilin-Null Mice Are Accompanied by Increased G Protein Coupling to the α2A-Adrenergic Receptor

R. Lu, Y. Chen, C. Cottingham, N. Peng, K. Jiao, L. E. Limbird, J. M. Wyss and Q. Wang
Molecular Pharmacology August 1, 2010, 78 (2) 279-286; DOI: https://doi.org/10.1124/mol.110.065300

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Research ArticleArticle

Enhanced Hypotensive, Bradycardic, and Hypnotic Responses to α2-Adrenergic Agonists in Spinophilin-Null Mice Are Accompanied by Increased G Protein Coupling to the α2A-Adrenergic Receptor

R. Lu, Y. Chen, C. Cottingham, N. Peng, K. Jiao, L. E. Limbird, J. M. Wyss and Q. Wang
Molecular Pharmacology August 1, 2010, 78 (2) 279-286; DOI: https://doi.org/10.1124/mol.110.065300
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