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Molecular Pharmacology

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Research ArticleArticle

Genetic Dissection of α2-Adrenoceptor Functions in Adrenergic versus Nonadrenergic Cells

Ralf Gilsbach, Christoph Röser, Nadine Beetz, Marc Brede, Kerstin Hadamek, Miriam Haubold, Jost Leemhuis, Melanie Philipp, Johanna Schneider, Michal Urbanski, Bela Szabo, David Weinshenker and Lutz Hein
Molecular Pharmacology May 2009, 75 (5) 1160-1170; DOI: https://doi.org/10.1124/mol.109.054544
Ralf Gilsbach
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Christoph Röser
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Nadine Beetz
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Marc Brede
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Kerstin Hadamek
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Miriam Haubold
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Jost Leemhuis
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Melanie Philipp
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Johanna Schneider
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Michal Urbanski
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Bela Szabo
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David Weinshenker
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Lutz Hein
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Abstract

α2-Adrenoceptors mediate diverse functions of the sympathetic system and are targets for the treatment of cardiovascular disease, depression, pain, glaucoma, and sympathetic activation during opioid withdrawal. To determine whether α2-adrenoceptors on adrenergic neurons or α2-adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of α2-agonists, we used the dopamine β-hydroxylase (Dbh) promoter to drive expression of α2A-adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-α2A transgenic mice were crossed with double knockout mice lacking both α2A- and α2C-receptors to generate lines with selective expression of α2A-autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express α2A- and α2C-receptors in both adrenergic and nonadrenergic cells, and α2A/α2C double-knockout mice, which do not express these receptors in any cell type. We were surprised to find that only a few functions previously ascribed to α2-adrenoceptors were mediated by receptors on adrenergic neurons, including feedback inhibition of norepinephrine release from sympathetic nerves and spontaneous locomotor activity. Other agonist effects, including analgesia, hypothermia, sedation, and anesthetic-sparing, were mediated by α2-receptors in nonadrenergic cells. In dopamine β-hydroxylase knockout mice lacking norepinephrine, the α2-agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of α2-adrenoceptor stimulation is not mediated via autoreceptor-mediated inhibition of norepinephrine release. The present study paves the way for a revision of the current view of the α2-adrenergic receptors, and it provides important new considerations for future drug development.

Footnotes

  • This work was supported by the Deutsche Forschungsgemeinschaft DFG (Grant HE 2073/3-1) and the DFG excellence cluster BIOSS.

  • ABBREVIATIONS: A(+/+), wild-type murine α2A-adrenoceptor gene; A(-/-), null allele of the murine α2A-adrenoceptor gene; Adra2a, Adra2b, Adra2c, murine genes encoding α2A-, α2B-, or α2C-adrenoceptors; Dbh, dopamine β-hydroxylase; SCG, superior cervical ganglia; Tg, transgenic line; CNS, central nervous system; LORR, loss of righting reflex; TH, tyrosine hydroxylase; PCR, polymerase chain reaction; qPCR, qualitative polymerase chain reaction; RT-PCR, reverse transcription-polymerase chain reaction; DSP-4, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride; RX821002, 2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole hydrochloride; UK14,304, brimonidine.

    • Received January 3, 2009.
    • Accepted February 27, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (5)
Molecular Pharmacology
Vol. 75, Issue 5
1 May 2009
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Research ArticleArticle

Genetic Dissection of α2-Adrenoceptor Functions in Adrenergic versus Nonadrenergic Cells

Ralf Gilsbach, Christoph Röser, Nadine Beetz, Marc Brede, Kerstin Hadamek, Miriam Haubold, Jost Leemhuis, Melanie Philipp, Johanna Schneider, Michal Urbanski, Bela Szabo, David Weinshenker and Lutz Hein
Molecular Pharmacology May 1, 2009, 75 (5) 1160-1170; DOI: https://doi.org/10.1124/mol.109.054544

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Research ArticleArticle

Genetic Dissection of α2-Adrenoceptor Functions in Adrenergic versus Nonadrenergic Cells

Ralf Gilsbach, Christoph Röser, Nadine Beetz, Marc Brede, Kerstin Hadamek, Miriam Haubold, Jost Leemhuis, Melanie Philipp, Johanna Schneider, Michal Urbanski, Bela Szabo, David Weinshenker and Lutz Hein
Molecular Pharmacology May 1, 2009, 75 (5) 1160-1170; DOI: https://doi.org/10.1124/mol.109.054544
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