报告题目：Cullin3-RING ligases are essential mediators for heterologous sensitization of adenylyl cyclase

报 告 人：丁众（Purdue University）

报告时间：2019年5月7日（星期二）15:30

报告地点：药学院云轩楼1323会议室

报告摘要：

Heterologous sensitization of adenylyl cyclase (AC) is revealed as enhanced or exaggerated AC/cAMP signaling that occurs following persistent activation of Gαi/o-coupled receptors. This paradoxical phenomenon was discovered more than forty years ago and is associated with drug dependence and behavioral sensitization. However, the underlying molecular mechanisms of heterologous sensitization remain largely unknown. Herein, we performed a genome-wide cell-based RNA interference (RNAi) screen as an unbiased approach to identify genes associated with heterologous sensitization of AC in a cellular model. Following a series of validation and confirmation assays, three genes: CUL3, NEDD8, and RBX1 that ultimately form an E3 ligase complex were identified as specific modulators for heterologous sensitization of AC. General proteasome inhibitors, MG-132 and bortezomib mimicked the effects of gene knockdown consistent with the downstream actions of this complex. Moreover,the specific nedd8-activating enzyme inhibitor, MLN4924 (Pevonedistat), was potent and efficacious in blocking the development of D2 dopamine receptor-induced heterologous sensitization of endogenous and recombinant AC isoforms including AC1, AC2, AC5, and AC6. Together, genetic and pharmacological approaches identified cullin3-RING ligases and protein degradation as modulators of heterologous sensitization of AC.