The α(1C)-adrenergic receptor: Characterization of signal transduction pathways and mammalian tissue heterogeneity

Published

Journal Article

We recently reported the cloning of a novel α1-adrenergic receptor (AR), the α(1C)AR. By transient and stable expression of the α(1C)AR and the previously cloned α(1B)AR 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 α(1C)- and α(1B)ARs primarily couple to phospholipase C via a pertussis toxin-insensitive GTP-binding protein, leading to the release of calcium from intracellular stores. Even though α(1C)- and α(1B)ARs activate polyphosphoinositide hydrolysis by similar biochemical mechanisms, the α(1C)AR couples to phospholipase C more efficiently than does the α(1B)AR; activation of the α(1C)AR results in a 2-3-fold greater increase in inositol phosphates, compared with the α(1B)AR. Both α1AR 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 α(1C)AR to stimulate phospholipase C, compared with the α(1B)AR. In addition, methoxamine is almost a full agonist at the α(1C)AR, whereas it can only weakly activate the α(1B)AR. 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 α(1B)AR is present in several rat tissues, including heart, liver, brain, kidney, lung, and spleen, whereas the α(1C)AR is not present in any rat tissue studied. The α(1B)AR is also present in rabbit aorta, heart, spleen, and kidney (and absent in rabbit liver), whereas the α(1C)AR is present in rabbit liver. Our results indicate that the cloning and expression of different α1AR subtypes represents a valuable tool to elucidate functional correlates of α1AR heterogeneity.

Duke Authors

Cited Authors

  • Schwinn, DA; Page, SO; Middleton, JP; Lorenz, W; Liggett, SB; Yamamoto, K; Lapetina, EG; Caron, MG; Lefkowitz, RJ; Cotecchia, S

Published Date

  • January 1, 1991

Published In

Volume / Issue

  • 40 / 5

Start / End Page

  • 619 - 626

International Standard Serial Number (ISSN)

  • 0026-895X

Citation Source

  • Scopus