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Multiple Independent Effects of Beta‐arrestins 1 & 2 in Protease Activated Receptor‐2 (PAR‐2) desensitization, internalization and signaling
Author(s) -
Kumar Puneet,
Mathur Maneesh,
Lau Michael,
DeFea Kathryn
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a246-a
Subject(s) - internalization , arrestin , microbiology and biotechnology , desensitization (medicine) , g protein coupled receptor , signal transduction , homologous desensitization , receptor , g protein coupled receptor kinase , extracellular , biology , chemistry , biochemistry
Protease Activated Receptor‐2 (PAR‐2) is a G Protein Coupled Receptor (GPCR), whose ligand is tethered to its N‐terminus and is activated only when it's N‐terminus is removed by an extracellular protease. Upon activation, PAR‐2 couples to Gq to mobilize intracellular calcium, leading to activation of both Phophatidyl Inositol 3 Kinase (PI3K) and Extracellular signal Regulated Kinase (ERK1/2). Paradoxically, PAR‐2‐evoked ERK1/2 activation requires beta‐arrestins 1 and 2, which are traditionally known to play a role in the desensitization and the internalization of receptors. Recent studies have demonstrated that beta‐arrestins can also mediate & generate independent signaling, but a distinct role of each individual beta‐arrestin in PAR‐2 desensitization, internalization and signaling has not been elucidated. Here we show that each isoform of beta‐arrestin can mediate the internalization, desensitization & the downstream signaling response following PAR‐2 activation. However, while beta‐arrestin‐1 is required for early, beta‐arrestin‐2 is required for prolonged receptor internalization and ERK1/2 activation. Furthermore, beta‐arrestin‐1 is sufficient to target a pool of PAR‐2 to lysosomes, while beta‐arrestin‐2 does not. These studies suggest that beta‐arrestins are not redundant in PAR‐2 signaling but work cooperatively to elicit specific downstream responses. α