TY - JOUR
T1 - Regulation of the cellular localization and signaling properties of the α(1B)- and α(1D)-adrenoceptors by agonists and inverse agonists
AU - McCune, Dan F.
AU - Edelmann, Stephanie E.
AU - Olges, Jennifer R.
AU - Post, Ginell R.
AU - Waldrop, Bruce A.
AU - Waugh, David J.J.
AU - Perez, Dianne M.
AU - Piascik, Michael T.
PY - 2000
Y1 - 2000
N2 - The regulation of the cellular distribution and intracellular signaling properties of the α(1B)- and α(1D)- adrenoceptor (α1-AR) subtypes was examined in stably transfected Rat 1 fibroblasts. In unstimulated cells, α(1B)-AR expression was noted primarily on the cell surface. Treatment with phenylephrine induced internalization of the α(1B)-AR and promoted association with arrestin 2. The internalized α(1B)-AR colocalized with the transferrin receptor, an endosomal marker. In unstimulated fibroblasts, the α(1D)-AR was detected in a perinuclear orientation and was colocalized with arrestin 2 in a compartment also containing the transferrin receptor. After treatment with prazosin, which exhibits inverse agonist properties, the α(1D)-AR was redistributed from intracellular sites to the cellular periphery and was no longer associated with the transferrin receptor or arrestin 2. α(1D)-AR-expressing cells exhibited a high degree of basal activity for both inositol phosphate formation and extracellular signal regulated kinase (ERK), which was reduced by treatment with prazosin. In these cells, phenylephrine induced a dose-dependent increase in inositol phosphate formation but had no effect on ERK activity. In α(1B) -AR- expressing cells, phenylephrine stimulated both inositol phosphate formation and ERK activity. These data show that: 1) there are differences in the cellular localization of the α1-AR subtypes; 2) the α(1B)-AR exhibits expected G protein-coupled receptor activity regarding cellular localization, agonist-mediated internalization, and coupling to second messengers; and 3) the α(1D)-AR is constitutively active and, as a result, is localized to intracellular compartments involved in receptor recycling.
AB - The regulation of the cellular distribution and intracellular signaling properties of the α(1B)- and α(1D)- adrenoceptor (α1-AR) subtypes was examined in stably transfected Rat 1 fibroblasts. In unstimulated cells, α(1B)-AR expression was noted primarily on the cell surface. Treatment with phenylephrine induced internalization of the α(1B)-AR and promoted association with arrestin 2. The internalized α(1B)-AR colocalized with the transferrin receptor, an endosomal marker. In unstimulated fibroblasts, the α(1D)-AR was detected in a perinuclear orientation and was colocalized with arrestin 2 in a compartment also containing the transferrin receptor. After treatment with prazosin, which exhibits inverse agonist properties, the α(1D)-AR was redistributed from intracellular sites to the cellular periphery and was no longer associated with the transferrin receptor or arrestin 2. α(1D)-AR-expressing cells exhibited a high degree of basal activity for both inositol phosphate formation and extracellular signal regulated kinase (ERK), which was reduced by treatment with prazosin. In these cells, phenylephrine induced a dose-dependent increase in inositol phosphate formation but had no effect on ERK activity. In α(1B) -AR- expressing cells, phenylephrine stimulated both inositol phosphate formation and ERK activity. These data show that: 1) there are differences in the cellular localization of the α1-AR subtypes; 2) the α(1B)-AR exhibits expected G protein-coupled receptor activity regarding cellular localization, agonist-mediated internalization, and coupling to second messengers; and 3) the α(1D)-AR is constitutively active and, as a result, is localized to intracellular compartments involved in receptor recycling.
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U2 - 10.1124/mol.57.4.659
DO - 10.1124/mol.57.4.659
M3 - Article
C2 - 10727510
AN - SCOPUS:0034034073
SN - 0026-895X
VL - 57
SP - 659
EP - 666
JO - Molecular Pharmacology
JF - Molecular Pharmacology
IS - 4
ER -