Compartmentation of β2 -Adrenergic Receptor Stimulated cAMP Responses by Phosphodiesterases Type 2 and 3 in Cardiac Ventricular Myocytes.

Abstract:

BACKGROUND AND PURPOSE:In cardiac myocytes, cAMP produced by both β1 and β2 -adrenergic receptors (ARs) results in an increase in L-type Ca2+ channel activity and myocyte contraction. However, only cAMP produced by β1 ARs is able to enhance myocyte relaxation through phospholamban-dependent regulation of the sarco/endoplasmic reticulum Ca2+ -ATPase 2 (SERCA2). The purpose of this study was to test the hypothesis that β2 AR stimulation produces a cAMP signal that is unable to reach SERCA2, and determine what role, if any, phosphodiesterase (PDE) activity plays in this compartmentation. EXPERIMENTAL APPROACH:The cAMP responses produced by β1 and β2 AR stimulation were studied in adult rat ventricular myocytes using two different fluorescence resonance energy transfer (FRET)-based biosensors: Epac2-camps, which is expressed uniformly throughout the cytoplasm of the entire cell, and Epac2-αKAP, which is targeted to the SERCA2 signaling complex. KEY RESULTS:Selective activation of β1 or β2 ARs produces cAMP responses detected by Epac2-camps. However, only β1 AR stimulation produces a cAMP response detected by Epac2-αKAP. Yet, β2 AR stimulation was able to produce a cAMP signal detected by Epac2-αKAP in the presence of selective inhibition of PDE2 or PDE3, but not PDE4. CONCLUSION AND IMPLICATIONS:These results support the conclusion that cAMP produced by β2 AR stimulation is not able to reach subcellular locations where the SERCA2 pump is located. Furthermore, this compartmentalized response is due at least in part to PDE2 and PDE3 activity. Leveraging this discovery could lead to novel PDE-based therapeutic treatments aimed at correcting cardiac relaxation defects associated with certain forms of heart failure.

journal_name

Br J Pharmacol

authors

Rudokas MW,Post JP,Sataray-Rodriguez A,Sherpa RT,Moshal KS,Agarwal SR,Harvey RD

doi

10.1111/bph.15382

subject

Has Abstract

pub_date

2021-01-21 00:00:00

eissn

0007-1188

issn

1476-5381

pub_type

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