Assembly of an SAP97-AKAP79-cAMP-dependent protein kinase scaffold at the type 1 PSD-95/DLG/ZO1 motif of the human β1-adrenergic receptor generates a receptosome involved in receptor recycling and networking

Lidia A. Gardner, Anjaparavanda P. Naren, Suleiman Bahouth

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Abstract

Appropriate trafficking of the β1-adrenergic receptor (β1-AR) after agonist-promoted internalization is crucial for the resensitization of its signaling pathway. Efficient recycling of the β1-AR required the binding of the protein kinase A anchoring protein-79 (AKAP79) to the carboxyl terminus of the β1-AR (Gardner, L. A., Tavalin, S. A., Goehring, A., Scott, J. D., and Bahouth, S. W. (2006) J. Biol. Chem. 281, 33537-33553). In this study we show that AKAP79 forms a complex with the type 1 PDZ-binding sequence (ESKV) at the extreme carboxyl terminus of the β1-AR, which is mediated by the membrane-associated guanylate kinase (MAGUK) protein SAP97. Thus, the PDZ and its associated SAP97-AKAP79 complex are involved in targeting the cyclic AMP-dependent protein kinase (PKA) to the β1-AR. The PDZ and its scaffold were required for efficient recycling of the β1-AR and for PKA-mediated phosphorylation of the β1-AR at Ser 312. Overexpression of the catalytic subunit of PKA or mutagenesis of Ser312 to the phosphoserine mimic aspartic acid both rescued the recycling of the trafficking-defective β1-ARΔPDZ mutant. Thus, trafficking signals transmitted from the PDZ-associated scaffold in the carboxyl terminus of the β1-AR to Ser312 in the 3rd intracellular loop (3rd IC) were paramount in setting the trafficking itinerary of the β1-AR. The data presented here show that a novel β1-adrenergic receptosome is organized at the β1-ARPDZto generate a scaffold essential for trafficking and networking of the β1-AR.

Original languageEnglish (US)
Pages (from-to)5085-5099
Number of pages15
JournalJournal of Biological Chemistry
Volume282
Issue number7
DOIs
StatePublished - Feb 16 2007

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Endosomes
Cyclic AMP-Dependent Protein Kinases
Scaffolds
Adrenergic Receptors
Recycling
Protein Kinases
Guanylate Kinases
Phosphoserine
Adrenergic Agonists
Mutagenesis
Phosphorylation
Aspartic Acid
Adrenergic Agents
Catalytic Domain
Carrier Proteins
Proteins

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Assembly of an SAP97-AKAP79-cAMP-dependent protein kinase scaffold at the type 1 PSD-95/DLG/ZO1 motif of the human β1-adrenergic receptor generates a receptosome involved in receptor recycling and networking",
abstract = "Appropriate trafficking of the β1-adrenergic receptor (β1-AR) after agonist-promoted internalization is crucial for the resensitization of its signaling pathway. Efficient recycling of the β1-AR required the binding of the protein kinase A anchoring protein-79 (AKAP79) to the carboxyl terminus of the β1-AR (Gardner, L. A., Tavalin, S. A., Goehring, A., Scott, J. D., and Bahouth, S. W. (2006) J. Biol. Chem. 281, 33537-33553). In this study we show that AKAP79 forms a complex with the type 1 PDZ-binding sequence (ESKV) at the extreme carboxyl terminus of the β1-AR, which is mediated by the membrane-associated guanylate kinase (MAGUK) protein SAP97. Thus, the PDZ and its associated SAP97-AKAP79 complex are involved in targeting the cyclic AMP-dependent protein kinase (PKA) to the β1-AR. The PDZ and its scaffold were required for efficient recycling of the β1-AR and for PKA-mediated phosphorylation of the β1-AR at Ser 312. Overexpression of the catalytic subunit of PKA or mutagenesis of Ser312 to the phosphoserine mimic aspartic acid both rescued the recycling of the trafficking-defective β1-ARΔPDZ mutant. Thus, trafficking signals transmitted from the PDZ-associated scaffold in the carboxyl terminus of the β1-AR to Ser312 in the 3rd intracellular loop (3rd IC) were paramount in setting the trafficking itinerary of the β1-AR. The data presented here show that a novel β1-adrenergic receptosome is organized at the β1-ARPDZto generate a scaffold essential for trafficking and networking of the β1-AR.",
author = "Gardner, {Lidia A.} and Naren, {Anjaparavanda P.} and Suleiman Bahouth",
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AU - Bahouth, Suleiman

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N2 - Appropriate trafficking of the β1-adrenergic receptor (β1-AR) after agonist-promoted internalization is crucial for the resensitization of its signaling pathway. Efficient recycling of the β1-AR required the binding of the protein kinase A anchoring protein-79 (AKAP79) to the carboxyl terminus of the β1-AR (Gardner, L. A., Tavalin, S. A., Goehring, A., Scott, J. D., and Bahouth, S. W. (2006) J. Biol. Chem. 281, 33537-33553). In this study we show that AKAP79 forms a complex with the type 1 PDZ-binding sequence (ESKV) at the extreme carboxyl terminus of the β1-AR, which is mediated by the membrane-associated guanylate kinase (MAGUK) protein SAP97. Thus, the PDZ and its associated SAP97-AKAP79 complex are involved in targeting the cyclic AMP-dependent protein kinase (PKA) to the β1-AR. The PDZ and its scaffold were required for efficient recycling of the β1-AR and for PKA-mediated phosphorylation of the β1-AR at Ser 312. Overexpression of the catalytic subunit of PKA or mutagenesis of Ser312 to the phosphoserine mimic aspartic acid both rescued the recycling of the trafficking-defective β1-ARΔPDZ mutant. Thus, trafficking signals transmitted from the PDZ-associated scaffold in the carboxyl terminus of the β1-AR to Ser312 in the 3rd intracellular loop (3rd IC) were paramount in setting the trafficking itinerary of the β1-AR. The data presented here show that a novel β1-adrenergic receptosome is organized at the β1-ARPDZto generate a scaffold essential for trafficking and networking of the β1-AR.

AB - Appropriate trafficking of the β1-adrenergic receptor (β1-AR) after agonist-promoted internalization is crucial for the resensitization of its signaling pathway. Efficient recycling of the β1-AR required the binding of the protein kinase A anchoring protein-79 (AKAP79) to the carboxyl terminus of the β1-AR (Gardner, L. A., Tavalin, S. A., Goehring, A., Scott, J. D., and Bahouth, S. W. (2006) J. Biol. Chem. 281, 33537-33553). In this study we show that AKAP79 forms a complex with the type 1 PDZ-binding sequence (ESKV) at the extreme carboxyl terminus of the β1-AR, which is mediated by the membrane-associated guanylate kinase (MAGUK) protein SAP97. Thus, the PDZ and its associated SAP97-AKAP79 complex are involved in targeting the cyclic AMP-dependent protein kinase (PKA) to the β1-AR. The PDZ and its scaffold were required for efficient recycling of the β1-AR and for PKA-mediated phosphorylation of the β1-AR at Ser 312. Overexpression of the catalytic subunit of PKA or mutagenesis of Ser312 to the phosphoserine mimic aspartic acid both rescued the recycling of the trafficking-defective β1-ARΔPDZ mutant. Thus, trafficking signals transmitted from the PDZ-associated scaffold in the carboxyl terminus of the β1-AR to Ser312 in the 3rd intracellular loop (3rd IC) were paramount in setting the trafficking itinerary of the β1-AR. The data presented here show that a novel β1-adrenergic receptosome is organized at the β1-ARPDZto generate a scaffold essential for trafficking and networking of the β1-AR.

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