Phosphodiesterase 4 interacts with the 5-HT4(b) receptor to regulate cAMP signaling

Weninger, S., Van Craenenbroeck, K., Cameron, R., Vandeput, F., Movsesian, M.A., Baillie, G.S. and Lefebvre, R.A. (2014) Phosphodiesterase 4 interacts with the 5-HT4(b) receptor to regulate cAMP signaling. Cellular Signalling, 26(11), pp. 2573-2582. (doi:10.1016/j.cellsig.2014.07.027) (PMID:25101859)

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Abstract

Phosphodiesterase (PDE) 3 and PDE4, which degrade cyclic adenosine monophosphate (cAMP), are important regulators of 5-hydroxytryptamine (5-HT) 4 receptor signaling in cardiac tissue. Therefore, we investigated whether they interact with the 5-HT4(b) receptor, and whether A-kinase anchoring proteins (AKAPs), scaffolding proteins that bind to the regulatory subunit of protein kinase A (PKA) and contribute to the spacial-temporal control of cAMP signaling, are involved in the regulation of 5-HT4(b) receptor signaling. By measuring PKA activity in the absence and presence of PDE3 and PDE4 inhibitiors, we found that constitutive signaling of the overexpressed HA-tagged 5-HT4(b) receptor in HEK293 cells is regulated predominantly by PDE4, with a secondary role for PDE3 that is unmasked in the presence of PDE4 inhibition. Overexpressed PDE4D3 and PDE3A1, and to a smaller extent PDE4D5 co-immunoprecipitate constitutively with the 5-HT4(b) receptor. PDE activity measurements in immunoprecipitates of the 5-HT4(b) receptor confirm the association of PDE4D3 with the receptor and provide evidence that the activity of this PDE may be increased upon receptor stimulation with 5-HT. A possible involvement of AKAPs in 5-HT4(b) receptor signaling was uncovered in experiments using the St-Ht31 inhibitor peptide, which disrupts the interaction of AKAPs with PKA. However, St-Ht31 did not influence 5-HT4(b) receptor-stimulated PKA activity, and endogenous AKAP79 and gravin were not found in immunoprecipitates of the 5-HT4(b) receptor. In conclusion, we found that both PDE3A1 and PDE4D3 are integrated into complexes that contain the 5-HT4(b) receptor and may thereby regulate 5-HT4(b) receptor-mediated signaling.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baillie, Professor George and Cameron, Mr Ryan
Authors: Weninger, S., Van Craenenbroeck, K., Cameron, R., Vandeput, F., Movsesian, M.A., Baillie, G.S., and Lefebvre, R.A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Cellular Signalling
Publisher:Elsevier Inc.
ISSN:0898-6568
ISSN (Online):1873-3913

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
438301Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targetsMiles HouslayMedical Research Council (MRC)G0600765RI NEUROSCIENCE & PSYCHOLOGY