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RE Link, MS Stevens, M Kulatunga, M Scheinin, GS Barsh and BK Kobilka
Department of Molecular and Cellular Physiology, Stanford University, California 94305, USA.
alpha 2-Adrenergic receptors (alpha 2-ARs) regulate a wide range of physiological functions and are targets for clinically important antihypertensive and anesthetic agents. Three genes encoding alpha 2-AR subtypes have been cloned in humans and mice, but the physiological significance of each subtype has not been completely characterized. The available agonist and antagonist compounds are not sufficiently subtype selective to allow the unambiguous dissection of these receptors in vivo. As an alternative approach, we have used gene targeting in embryonic stem cells to disrupt the Adra2c gene, which encodes the alpha 2c-AR subtype in mice. Adra2c-/Adra2c- animals do not express a functional alpha 2c-AR transcript, as detected by Northern blotting or reverse transcription-polymerase chain reaction analysis. In addition, these mice have markedly reduced [3H]rauwolscine binding in their caudate putamen and in other brain regions normally expressing Adra2c binding sites. Adra2c-/Adra2c- mice, however, are viable and fertile and appear grossly normal. Expression levels of Adra2a and Adra2b mRNA in brain and kidney are not altered by the Adra2c knockout. These data suggest that up-regulation of Adra2a or Adra2b does not compensate for the Adra2c deficiency and that the receptor encoded by Adra2c is not required for normal mouse development or for survival in a laboratory environment.
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