G Protein-coupled Receptor Kinase 5 Regulates β1-Adrenergic Receptor Association with PSD-95

Hu, Liaoyuan A.; Chen, Wei; Premont, Richard T.; Cong, Mei; Lefkowitz, Robert J.

doi:10.1074/jbc.m107297200

Cited by 60 publications

(37 citation statements)

References 39 publications

(64 reference statements)

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“…Association with cytoplasmic scaffold proteins is another factor that might potentially regulate heterodimer formation. The ␤ 1 -adrenergic receptor is known to associate with PSD-95/Discs-large/ZO-1 homology domain-containing scaffold proteins such as PSD-95 (14,41,42) and MAGI-2 (14). However, we have not observed any significant effects of PSD-95 or MAGI-2 coexpression on the extent of either ␤ 1 AR/␤ 1 AR homodimerization (14) or ␣ 2A AR/ ␤ 1 AR heterodimerization (data not shown).…”

Section: Discussioncontrasting

confidence: 42%

Heterodimerization of α2A- and β1-Adrenergic Receptors

Castleberry

et al. 2003

Journal of Biological Chemistry

112

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The physiological actions of epinephrine and norepinephrine are mediated via the activation of the following three distinct classes of G protein-coupled receptors (GPCR) 1 : ␣ 1 -, ␣ 2 -, and ␤-adrenergic receptors. Each class of adrenergic receptor (AR) is comprised of three closely related subtypes as follows: ␣ 1A -, ␣ 1B -, and ␣ 1D AR, which couple primarily to G q to stimulate phospholipase activity; ␣ 2A -, ␣ 2B -, and ␣ 2C AR, which couple primarily to G i to inhibit adenylyl cyclase activity; and ␤ 1 -, ␤ 2 -, and ␤ 3 AR, which couple primarily to G s to stimulate adenylyl cyclase activity (1). The adrenergic receptor subtypes are differentially distributed across various tissues, and tissue responses to epinephrine and norepinephrine are believed to be dependent upon the relative ratios of the various adrenergic receptors they express.Because ␤-and ␣ 2 -adrenergic receptors couple to G proteins with opposing actions on adenylyl cyclase activity, the two receptors might be expected to purely antagonize each other's signaling when they are co-stimulated in the same cell. However, it has been shown that ␣ 2 AR co-stimulation can in some cases paradoxically sensitize ␤-adrenergic signaling in brain tissue (2-4). Moreover, the pharmacological properties of ␤ARs in brain tissue are known to be regulated by ␣ 2 ARs (5, 6), and reciprocally the pharmacological properties of ␣ 2 ARs in brain tissue are known to regulated by ␤ARs (7,8). These examples of cross-talk and mutual regulation between ␤-and ␣ 2 -adrenergic receptors have been well known for more than 20 years, but the underlying molecular mechanisms remain unclear.GPCRs have traditionally been thought to exist as monomers, but recent studies (9) have revealed that they can exist in the plasma membrane as both homodimers and heterodimers. At present, a key question in this field is: how widespread is the phenomenon of receptor heterodimerization? The most clearcut case of the importance of GPCR heterodimerization comes from the GABA B receptor, a pharmacologically defined entity that is now known to be comprised of two distinct GPCRs, GABA B R1 and GABA B R2 (10). Because GABA B R1 and GAB-A B R2 are not functional when expressed by themselves, they represent a clear example of the physiological importance of receptor heterodimerization. Although other heptahelical receptors may not absolutely require heterodimerization to be functional in the same way that the GABA B receptor does, heterodimerization of other receptors may underlie some phenomena that are major question marks in our present understanding of neurotransmitter and hormone receptors, such as unexplained forms of cross-talk between different receptor subtypes.We wondered if the previously reported cross-talk between ␤ARs and ␣ 2 ARs in brain tissue might be due in part to a physical association between these two receptor types. Many early studies (11-13) of GPCR dimerization focused on the ␤ 2 AR. We have found recently (14) that the ␤ 1 AR also exhibits robust homodimerization in cells. Fu...

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Section: Discussioncontrasting

confidence: 42%

Heterodimerization of α2A- and β1-Adrenergic Receptors

Castleberry

et al. 2003

Journal of Biological Chemistry

112

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“…In accordance with this, phosphorylation of the inward rectifier K channel Kir 2.3 on the equivalent serine causes rapid dissociation of the channel from PSD-95 (6). Moreover, a recent report has demonstrated that overexpression of intact GPCR kinase 5 (GRK5) decreases ␤1-AR association with the PDZ domain of PSD-95 (26). This reduction of ␤1-AR-PSD-95 interaction is mimicked by receptor stimulation with an agonist, but a kinase-inactive GRK5 mutant has no effect on PSD-95 binding to ␤1-AR.…”

Section: Discussionmentioning

confidence: 73%

Direct Binding of the β1 Adrenergic Receptor to the Cyclic AMP-Dependent Guanine Nucleotide Exchange Factor CNrasGEF Leads to Ras Activation

Pak

Pham

Rotin

2002

Molecular and Cellular Biology

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G-protein-coupled receptors (GPCRs) can indirectly activate Ras primarily through the ␤␥ subunits of G proteins, which recruit c-Src, phosphatidylinositol 3-kinase, and Grb2-SOS. However, a direct interaction between a Ras activator (guanine nucleotide exchange factor [GEF]) and GPCRs that leads to Ras activation has never been demonstrated. We report here a novel mechanism for a direct GPCR-mediated Ras activation. The ␤1 adrenergic receptor (␤1-AR) binds to the PDZ domain of the cyclic AMP (cAMP)-dependent Ras exchange factor, CNrasGEF, via its C-terminal SkV motif. In cells heterologously expressing ␤1-AR and CNrasGEF, Ras is activated by the ␤1-AR agonist isoproterenol, and this activation is abolished in ␤1-AR mutants that cannot bind CNrasGEF or in CNrasGEF mutants lacking the catalytic CDC25 domain or cAMP-binding domain. Moreover, the activation is transduced via Gs␣ and not via G␤␥. In contrast to ␤1-AR, the ␤2-AR neither binds CNrasGEF nor activates Ras via CNrasGEF after agonist stimulation. These results suggest a model whereby the physical interaction between the ␤1-AR and CNrasGEF facilitates the transduction of Gs␣-induced cAMP signal into the activation of Ras. The present study provides the first demonstration of direct physical association between a Ras activator and a GPCR, leading to agonist-induced Ras activation G-protein-coupled receptors (GPCRs) have been classically known to transduce extracellular signals intracellularly by utilizing heterotrimeric G protein complexes comprised of ␣, ␤, and ␥ subunits. Agonist binding promotes a conformational change in GPCRs, leading to the release of ␤␥ and guanine nucleotide exchange on the ␣ subunit that loads it with GTP, which in turn can stimulate a number of intracellular second messengers, such as adenylyl cyclase and phospholipase C. However, this model alone cannot adequately explain the full range of effects of GPCRs, especially the stimulation of ty-

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“…β1AR also terminates in a PDZ-interacting sequence (ESKV) that is recognized by PSD-95 and MAGI-2, which respectively inhibits and enhances receptor Journal of Cell Science 117 (5) internalization (Hu et al, 2000;Xu et al, 2001). The interaction between PSD-95 and β 1AR is inhibited when the sequence is phosphorylated by GRK-5 (Hu et al, 2002). Both PSD-95 and MAGI-2 are only expressed in highly differentiated cells such as neurons where they function as post-synaptic scaffolding proteins.…”

Section: Discussionmentioning

confidence: 99%