Journal
EMBO JOURNAL
Volume 25, Issue 10, Pages 2051-2061Publisher
WILEY
DOI: 10.1038/sj.emboj.7601113
Keywords
AKAP; cAMP; microdomain; PDE4; PKA
Categories
Funding
- NIDDK NIH HHS [P01 DK054441, DK54441] Funding Source: Medline
- NINDS NIH HHS [R01 NS028389, NS28389] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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The spatiotemporal regulation of cAMP can generate microdomains just beneath the plasma membrane where cAMP increases are larger and more dynamic than those seen globally. Real-time measurements of cAMP using mutant cyclic nucleotide-gated ion channel biosensors, pharmacological tools and RNA interference (RNAi) were employed to demonstrate a subplasmalemmal cAMP signaling module in living cells. Transient cAMP increases were observed upon stimulation of HEK293 cells with prostaglandin E-1. However, pretreatment with selective inhibitors of type 4 phosphodiesterases (PDE4), protein kinase A (PKA) or PKA/A-kinase anchoring protein ( AKAP) interaction blocked an immediate return of subplasmalemmal cAMP to basal levels. Knockdown of specific membrane-associated AKAPs using RNAi identified gravin (AKAP250) as the central organizer of the PDE4 complex. Co-immunoprecipitation confirmed that gravin maintains a signaling complex that includes PKA and PDE4D. We propose that gravin-associated PDE4D isoforms provide a means to rapidly terminate subplasmalemmal cAMP signals with concomitant effects on localized ion channels or enzyme activities.
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