Degradation of the G protein-coupled receptor kinase 2 by the proteasome pathway

GRK2 is a ubiquitous member of the G; protein-coupled receptor kinase (GRK) family and has been shown to play a key role in determining the desensitiz ation and resensitization patterns of a variety of G protein-coupled recept ors. In this report, we show that GRK2 is actively degraded by the proteaso me proteolytic pathway, unveiling a new mechanism for the rapid regulation of its expression levels. Interestingly, activation of beta(2)-adrenergic r eceptors (beta(2)AR) markedly increases GRK2 ubiquitination and degradation through the proteasome pathway. In addition, blocking GRK2 degradation not ably alters beta(2)AR signaling and internalization, consistent with a rele vant physiological role for GRK2 proteasomal degradation. Activity-dependen t modulation of GRK2 cellular levels emerges as an important mechanism for modulating the cellular response to agonists acting through G protein coupl ed receptors.