Sorting of β1-Adrenergic Receptors Is Mediated by Pathways That Are Either Dependent on or Independent of Type I PDZ, Protein Kinase A (PKA), and SAP97

Nooh, Mohammed M.; Chumpia, Maryanne; Hamilton, T.B.; Bahouth, Suleiman W.

doi:10.1074/jbc.m113.513481

Cited by 22 publications

(40 citation statements)

References 50 publications

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“…Nevertheless, SAP97 has been demonstrated to promote b 1 AR phosphorylation via cyclic AMP-dependent protein kinase (PKA), despite having no effect on b 1 AR-stimulated adenylyl cyclase activation and cAMP accumulation (Gardner et al, 2007). Additionally, SAP97 promotes recycling of b 1 AR by a mechanism that involves the formation of a complex among b 1 AR, PKA-anchoring protein 79, and PKA (Gardner et al, 2007;Nooh, et al, 2013Nooh, et al, , 2014. In contrast, SAP97 promotes membrane stabilization of the corticotropin-releasing factor (CRF) receptor 1 by suppressing CRFR1 endocytosis (Dunn et al, 2013).…”

Section: Gpcr-interacting Psd-95 Family Pdz Domain-mentioning

confidence: 99%

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

Dunn

Ferguson

2015

Mol Pharmacol

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G protein-coupled receptors (GPCRs) contribute to the regulation of every aspect of human physiology and are therapeutic targets for the treatment of numerous diseases. As a consequence, understanding the myriad of mechanisms controlling GPCR signaling and trafficking is essential for the development of new pharmacological strategies for the treatment of human pathologies. Of the many GPCR-interacting proteins, postsynaptic density protein of 95 kilodaltons, disc large, zona occludens-1 (PDZ) domain-containing proteins appear most abundant and have similarly been implicated in disease mechanisms. PDZ proteins play an important role in regulating receptor and channel protein localization within synapses and tight junctions and function to scaffold intracellular signaling protein complexes. In the current study, we review the known functional interactions between PDZ domain-containing proteins and GPCRs and provide insight into the potential mechanisms of action. These PDZ domain-containing proteins include the membraneassociated guanylate-like kinases [postsynaptic density protein of 95 kilodaltons; synapse-associated protein of 97 kilodaltons; postsynaptic density protein of 93 kilodaltons; synapse-associated protein of 102 kilodaltons; discs, large homolog 5; caspase activation and recruitment domain and membrane-associated guanylate-like kinase domain-containing protein 3; membrane protein, palmitoylated 3; calcium/calmodulin-dependent serine protein kinase; membrane-associated guanylate kinase protein (MAGI)-1, MAGI-2, and MAGI-3], Na 1 /H 1 exchanger regulatory factor proteins (NHERFs) (NHERF1, NHERF2, PDZ domaincontaining kidney protein 1, and PDZ domain-containing kidney protein 2), Golgi-associated PDZ proteins (Ga-binding protein interacting protein, C-terminus and CFTR-associated ligand), PDZ domain-containing guanine nucleotide exchange factors (GEFs) 1 and 2, regulator of G protein signaling (RGS)-homology-RhoGEFs (PDZ domain-containing RhoGEF and leukemia-associated RhoGEF), RGS3 and RGS12, spinophilin and neurabin-1, SRC homology 3 domain and multiple ankyrin repeat domain (Shank) proteins (Shank1, Shank2, and Shank3), partitioning defective proteins 3 and 6, multiple PDZ protein 1, Tamalin, neuronal nitric oxide synthase, syntrophins, protein interacting with protein kinase C a 1, syntenin-1, and sorting nexin 27.

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Section: Gpcr-interacting Psd-95 Family Pdz Domain-mentioning

confidence: 99%

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

Dunn

Ferguson

2015

Mol Pharmacol

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“…The addition of a single alanine residue after the type-1 PDZ at position +1 in the human β 1 -AR inactivated the PDZ-binding domain and inhibited the recycling of GPCR following their internalization by their respective agonists [18–19]. These data provide strong evidence for a primary role for the carboxy-terminal PDZ-interacting sequence in regulating the trafficking of internalized GPCR.…”

Section: Resultsmentioning

confidence: 89%

“…Also, there are reports that internal PDZ-binding domains were active in supporting the recycling of some GPCR [22]. Moreover, substituting the β 1 -AR PDZ-binding sequence with non-PDZ sequences derived from recycling GPCRs such as the μ-opioid receptor or dopamine 1 -receptor supported the recycling of these β 1 -AR chimeras in a PDZ-independent manner [18]. To find out if progressive elongation of the β 1 -AR would somehow facilitate it’s recycling, we fused stretches of 4, 6, 12 and 16 amino acids downstream of the β 1 -AR and determined their trafficking profiles by confocal microscopy (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of novel transplantable GPCR recycling motif for drug discovery

Nooh

Mancarella

Bahouth

2016

Biochemical Pharmacology

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β1-adrenergic receptor (β1-AR) agonists and antagonists are widely used in the treatment of major cardiovascular diseases such as heart failure and hypertension. The β1-AR like other G protein-couple receptors (GPCR) is endocytosed in response to intense agonist activation. Recycling of the agonist-internalized β1-AR is dependent on its carboxy-terminal type-1 PSD-95/DLG/ZO1 (PDZ) and on phospho-serine312 in the third intracellular loop of the β1-AR. Progressive elongation of the β1-AR at its C-tail inactivated the PDZ-biding domain and inhibited the recycling of the β1-AR. However, fusing a twenty amino acid peptide derived from the multiple cloning region of the mammalian expression vector pCDNA3 to the C-tail of the β1-AR (β1-AR[+20]) produced a chimeric β1-AR that recycled rapidly and efficiently. The β1-AR[+20] recycled in a type-1 PDZ and phospho-Ser312-independent manner, indicating that this peptide provided a general GPCR recycling signal. Fusing the enhanced yellow fluorescent protein (EYFP) down-stream of β1-AR[+20] generated a β1-AR-EYFP chimera that was expressed on the membrane and recycled efficiently after agonist-induced internalization. This construct trafficked in a PDZ-SNX27/retromer-independent manner. We also fused EYFP to the N-terminus of the β1-AR to created EYFP-WT β1-AR. This construct recycled in PDZ and SNX27/retromer dependent manner. These β1-AR-EYFP constructs would be useful for high throughput screening (HTS) programs to identify new entities that would interfere with the recycling of agonist internalized GPCR that traffic in PDZ-dependent vs. PDZ-independent roadmaps.

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“…SAP97) at the sarcolemma (11,24). Even after internalization, SAP97 works together with AKAP150/79 to facilitate ␤ 1 AR recycling to the cell surface by PKA-mediated phosphorylation of the receptor at serine 312 (25)(26)(27). Together, the processes enable ␤ 1 ARs to access available agonists at the extracellular space and signal to G protein.…”

Section: Discussionmentioning

confidence: 99%

A Long Lasting β1 Adrenergic Receptor Stimulation of cAMP/Protein Kinase A (PKA) Signal in Cardiac Myocytes

Kim

Soto

et al. 2014

Journal of Biological Chemistry

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Background: Transient ␤ 1 AR activation remains at odds with long lasting cellular and physiological responses. Results: The agonist-occupied ␤ 1 AR continuously signals to adenylyl cyclase (AC) to produce cAMP in both cardiac myocytes and neurons for more than 8 h, which is masked by receptor-associated PDE4D8. Conclusion: Stimulation of ␤ 1 AR induces long-lasting cAMP production in the heart for ligand-induced physiological responses. Significance: We show a novel mechanism to understand persistent ␤ 1 AR signaling in the heart.

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Sorting of β1-Adrenergic Receptors Is Mediated by Pathways That Are Either Dependent on or Independent of Type I PDZ, Protein Kinase A (PKA), and SAP97

Cited by 22 publications

References 50 publications

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

PDZ Protein Regulation of G Protein–Coupled Receptor Trafficking and Signaling Pathways

Identification of novel transplantable GPCR recycling motif for drug discovery

A Long Lasting β1 Adrenergic Receptor Stimulation of cAMP/Protein Kinase A (PKA) Signal in Cardiac Myocytes

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