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Vol. 56, Issue 2, 316-324, August 1999
1B-Adrenergic, and
A1 Adenosine Receptor-Mediated Responses
Consorzio Mario Negri Sud, Istituto di Ricerche Farmacologiche
"Mario Negri," Santa Maria Imbaro, Italy
G protein-coupled receptor kinases (GRKs) play a key role in the
process of receptor homologous desensitization. In the present study,
we address the question of whether a variety of receptors coupled to
different G protein subtypes and naturally expressed on the same cell
are selectively regulated by GRK2. The signaling stimulated by
thyrotropin (TSH), 
1B-adrenergic, and A1
adenosine receptors was studied in FRTL-5 cells permanently transfected to overexpress GRK2 and GRK2-K220R, a kinase dead GRK dominant negative
mutant. In FRTL-5 overexpressing GRK2, TSH-induced cyclic AMP response
was attenuated, indicating that TSH receptor is desensitized by this
kinase. Consistently, FRTL-5 cells overexpressing GRK2-K220R show
increased TSH-induced cyclic AMP response, demonstrating that this
receptor is under tonic control by GRK. Unlike TSH receptor, 1B-adrenergic receptor response was unaffected in FRTL-5
overexpressing GRK2 and GRK2-K220R. When A1 adenosine
receptors were stimulated, Gi
-mediated cyclic AMP
inhibition was totally unaffected by overexpression of either GRK2 or
GRK2-K220R. By contrast, G
-mediated response
(activation of mitogen-activated protein kinases) was efficiently
desensitized by GRK2 but was unaffected by GRK2-K220R overexpression.
The present study documents that overexpression of GRK2 results in a
selective regulation of different G protein-coupled receptors expressed
on the same cell and that this kinase can regulate preferentially only
one of the different pathways activated by the same receptor. The
preferential regulation of the A1 adenosine receptor-stimulated mitogen-activated protein kinases by GRK2 indicates
that this kinase can have additional regulatory effects on
G-stimulated pathways, possibly through direct
binding and regulation of the receptor-G complex.
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