Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gßγ complex.
Proc Natl Acad Sci U S A
; 110(4): 1530-5, 2013 Jan 22.
Article
em En
| MEDLINE
| ID: mdl-23297229
ABSTRACT
G protein-coupled receptors (GPCRs) participate in ubiquitous transmembrane signal transduction processes by activating heterotrimeric G proteins. In the current "canonical" model of GPCR signaling, arrestins terminate receptor signaling by impairing receptor-G-protein coupling and promoting receptor internalization. However, parathyroid hormone receptor type 1 (PTHR), an essential GPCR involved in bone and mineral metabolism, does not follow this conventional desensitization paradigm. ß-Arrestins prolong G protein (G(S))-mediated cAMP generation triggered by PTH, a process that correlates with the persistence of arrestin-PTHR complexes on endosomes and which is thought to be associated with prolonged physiological calcemic and phosphate responses. This presents an inescapable paradox for the current model of arrestin-mediated receptor-G-protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and the Gßγ dimer in response to PTH stimulation, which in turn causes an accelerated rate of G(S) activation and increases the steady-state levels of activated G(S), leading to prolonged generation of cAMP. This work provides the mechanistic basis for an alternative model of GPCR signaling in which arrestins contribute to sustaining the effect of an agonist hormone on the receptor.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Arrestinas
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Subunidades beta da Proteína de Ligação ao GTP
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Subunidades gama da Proteína de Ligação ao GTP
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Receptores Acoplados a Proteínas G
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Receptor Tipo 1 de Hormônio Paratireóideo
Limite:
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article