Arrestin-dependent nuclear export of phosphodiesterase 4D promotes GPCR-induced nuclear cAMP signaling required for learning and memory

Author:

Martinez Joseph M.1ORCID,Shen Ao12ORCID,Xu Bing13,Jovanovic Aleksandra1ORCID,de Chabot Josephine1ORCID,Zhang Jin4ORCID,Xiang Yang K.13ORCID

Affiliation:

1. Department of Pharmacology, University of California at Davis, Davis, CA 95616, USA.

2. School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou 511436, China.

3. VA Northern California Health Care System, Mather, CA 95655, USA.

4. Department of Pharmacology, University of California at San Diego, San Diego, CA 92093, USA.

Abstract

G protein–coupled receptors (GPCRs) promote the expression of immediate early genes required for learning and memory. Here, we showed that β 2 -adrenergic receptor (β 2 AR) stimulation induced the nuclear export of phosphodiesterase 4D5 (PDE4D5), an enzyme that degrades the second messenger cAMP, to enable memory consolidation. We demonstrated that the endocytosis of β 2 AR phosphorylated by GPCR kinases (GRKs) mediated arrestin3-dependent nuclear export of PDE4D5, which was critical for promoting nuclear cAMP signaling and gene expression in hippocampal neurons for memory consolidation. Inhibition of the arrestin3-PDE4D5 association prevented β 2 AR-induced nuclear cAMP signaling without affecting receptor endocytosis. Direct PDE4 inhibition rescued β 2 AR-induced nuclear cAMP signaling and ameliorated memory deficits in mice expressing a form of the β 2 AR that could not be phosphorylated by GRKs. These data reveal how β 2 AR phosphorylated by endosomal GRK promotes the nuclear export of PDE4D5, leading to nuclear cAMP signaling, changes in gene expression, and memory consolidation. This study also highlights the translocation of PDEs as a mechanism to promote cAMP signaling in specific subcellular locations downstream of GPCR activation.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Cell Biology,Molecular Biology,Biochemistry

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3