Targeting of Cyclic AMP Degradation to β ₂ -Adrenergic Receptors by β-Arrestins

Abstract

Catecholamines signal through the beta2-adrenergic receptor by promoting production of the second messenger adenosine 3',5'-monophosphate (cAMP). The magnitude of this signal is restricted by desensitization of the receptors through their binding to beta-arrestins and by cAMP degradation by phosphodiesterase (PDE) enzymes. We show that beta-arrestins coordinate both processes by recruiting PDEs to activated beta2-adrenergic receptors in the plasma membrane of mammalian cells. In doing so, the beta-arrestins limit activation of membrane-associated cAMP-activated protein kinase by simultaneously slowing the rate of cAMP production through receptor desensitization and increasing the rate of its degradation at the membrane.

The human near‐term myometrial β3‐adrenoceptor but not the β2‐adrenoceptor is resistant to desensitisation after sustained agonist stimulation

“…We might also hypothesise that an increased degradation of cAMP by PDE4 could play a role in b 2 -AR desensitisation. This mechanism has been well documented in several systems including S49 lymphoma cells, platelets, hepatocytes, adipocytes and Sertoli cells (for review, Giembycz, 1996;Perry et al, 2002). It has been demonstrated, in different human blood cells, that treatment with either b 2 -AR agonists (Manning et al, 1996;Seybold et al, 1998;Ortiz et al, 2000) or with a cAMP structural analogue, 8-Bromo-cAMP, leads to an upregulation of PDE4 enzymes.…”

“…In human myometrium, among the five PDE families represented, it is now well established that the PDE4 family, specific for cAMP hydrolysis and inducible by its own substrate cAMP, is predominantly expressed (Leroy et al, 1989;Bardou et al, 1999). There is now defined evidence that cAMP induces an upregulation of PDE4, accelerating the degradation of this cyclic nucleotide (Perry et al, 2002). Interestingly, previous studies on cellular models such as U937 monocytes (Torphy et al, 1995) and human neutrophils (Ortiz et al, 2000) indicated that cAMP-PDE4 activity was increased after a treatment by b 2 -agonists.…”

β-Arrestin1 Mediates Insulin-like Growth Factor 1 (IGF-1) Activation of Phosphatidylinositol 3-Kinase (PI3K) and Anti-apoptosis

“…IGF-1 stimulates membrane PI3K␣ activity in ␤-arrestin1-containing B1 cells, but not in ␤-arrestin DKO cells. A, DKO mouse fibroblasts express no ␤-arrestin, whereas B1 cells express ␤-arrestin1 at endogenous levels (16). Cell lysates were subjected to PAGE and immunoblotted with an antibody specific for ␤-arrestin1 and ␤-arrestin2.…”

“…Given the central roles played by PI3Ks in cellular responses to receptor tyrosine kinase stimulation, we sought to assess the roles, if any, played by ␤-arrestins in IGF-1-mediated activation of PI3K. (16) were grown in Dulbecco's modified Eagle's medium, 10% fetal bovine serum, 100 units/ml penicillin, and 100 g/ml streptomycin. To establish genetically identical cell lines differing only in the level of ␤-arrestin1 expression, cells lacking ␤-arrestin were transfected with pcDNA3.1-Zeo (Invitrogen) or pcDNA3.1-␤-arrestin1-FLAG (17) using LipofectAMINE® to create DKO and B1 cells, respectively.…”

Protein–protein interactions of PDE4 family members — Functions, interactions and therapeutic value

“…This redistribution of β-arrestin to the receptor is associated with a co-redistribution of PDE4D5 to the receptor and local cAMP hydrolysis. Thus PDE4D contributes to terminating β-adrenoceptor signalling [32]. The β-adrenoceptor-induced rise in cAMP leads to PKA activation and PKA-catalysed phosphorylation of the receptor, which, in turn, switches receptor coupling from G s to the inhibitory G protein, G i .…”