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The alpha 1C-adrenergic receptor: characterization of signal transduction pathways and mammalian tissue heterogeneity.

Publication ,  Journal Article
Schwinn, DA; Page, SO; Middleton, JP; Lorenz, W; Liggett, SB; Yamamoto, K; Lapetina, EG; Caron, MG; Lefkowitz, RJ; Cotecchia, S
Published in: Mol Pharmacol
November 1991

We recently reported the cloning of a novel alpha 1-adrenergic receptor (AR), the alpha 1CAR. By transient and stable expression of the alpha 1CAR and the previously cloned alpha 1BAR in COS-7 and HeLa cells, respectively, we have now compared their ability to interact with major signal-transduction pathways (including polyphosphoinositide hydrolysis, intracellular calcium, and cAMP metabolism), as well as their mammalian tissue localization. Both alpha 1C- and alpha 1BARs primarily couple to phospholipase C via a pertussis toxin-insensitive GTP-binding protein, leading to the release of calcium from intracellular stores. Even though alpha 1C- and alpha 1BARs activate polyphosphoinositide hydrolysis by similar biochemical mechanisms, the alpha 1CAR couples to phospholipase C more efficiently than does the alpha 1BAR; activation of the alpha 1CAR results in a 2-3-fold greater increase in inositol phosphates, compared with the alpha 1BAR. Both alpha 1AR subtypes can also increase intracellular cAMP, by a mechanism that does not involve direct activation of adenylyl cyclase. In agreement with ligand binding data, the agonist methoxamine and the antagonist WB4101 are 10-fold more potent in activating or inhibiting, respectively, the ability of the alpha 1CAR to stimulate phospholipase C, compared with the alpha 1BAR. In addition, methoxamine is almost a full agonist at the alpha 1CAR, whereas it can only weakly activate the alpha 1BAR. Tissue localization, using Northern blot analysis of total and poly(A)+-selected RNA from rabbit tissues, revealed striking mammalian species heterogeneity. As previously described, the alpha 1BAR is present in several rat tissues, including heart, liver, brain, kidney, lung, and spleen, whereas the alpha 1CAR is not present in any rat tissue studied. The alpha 1BAR is also present in rabbit aorta, heart, spleen, and kidney (and absent in rabbit liver), whereas the alpha 1CAR is present in rabbit liver. Our results indicate that the cloning and expression of different alpha 1AR subtypes represents a valuable tool to elucidate functional correlates of alpha 1AR heterogeneity.

Duke Scholars

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

November 1991

Volume

40

Issue

5

Start / End Page

619 / 626

Location

United States

Related Subject Headings

  • Type C Phospholipases
  • Stereoisomerism
  • Signal Transduction
  • Receptors, Adrenergic, alpha
  • Rats
  • Rabbits
  • Phosphatidylinositols
  • Pharmacology & Pharmacy
  • Norepinephrine
  • Humans
 

Citation

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Schwinn, D. A., Page, S. O., Middleton, J. P., Lorenz, W., Liggett, S. B., Yamamoto, K., … Cotecchia, S. (1991). The alpha 1C-adrenergic receptor: characterization of signal transduction pathways and mammalian tissue heterogeneity. Mol Pharmacol, 40(5), 619–626.
Schwinn, D. A., S. O. Page, J. P. Middleton, W. Lorenz, S. B. Liggett, K. Yamamoto, E. G. Lapetina, M. G. Caron, R. J. Lefkowitz, and S. Cotecchia. “The alpha 1C-adrenergic receptor: characterization of signal transduction pathways and mammalian tissue heterogeneity.Mol Pharmacol 40, no. 5 (November 1991): 619–26.
Schwinn DA, Page SO, Middleton JP, Lorenz W, Liggett SB, Yamamoto K, et al. The alpha 1C-adrenergic receptor: characterization of signal transduction pathways and mammalian tissue heterogeneity. Mol Pharmacol. 1991 Nov;40(5):619–26.
Schwinn, D. A., et al. “The alpha 1C-adrenergic receptor: characterization of signal transduction pathways and mammalian tissue heterogeneity.Mol Pharmacol, vol. 40, no. 5, Nov. 1991, pp. 619–26.
Schwinn DA, Page SO, Middleton JP, Lorenz W, Liggett SB, Yamamoto K, Lapetina EG, Caron MG, Lefkowitz RJ, Cotecchia S. The alpha 1C-adrenergic receptor: characterization of signal transduction pathways and mammalian tissue heterogeneity. Mol Pharmacol. 1991 Nov;40(5):619–626.

Published In

Mol Pharmacol

ISSN

0026-895X

Publication Date

November 1991

Volume

40

Issue

5

Start / End Page

619 / 626

Location

United States

Related Subject Headings

  • Type C Phospholipases
  • Stereoisomerism
  • Signal Transduction
  • Receptors, Adrenergic, alpha
  • Rats
  • Rabbits
  • Phosphatidylinositols
  • Pharmacology & Pharmacy
  • Norepinephrine
  • Humans