Regulation of G Protein-Coupled Receptor Kinases

Penn, Raymond B.; Pronin, Alexey; Benovic, Jeffrey L.

doi:10.1016/s1050-1738(00)00053-0

Cited by 196 publications

(145 citation statements)

References 50 publications

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“…This leads to an uncoupling of the receptor from the G s -adenylyl cyclase system and, finally, to a decrease in β-AR responses to agonist stimulation. In the heart, three GRK isoforms are expressed: GRK2 (or βARK1), GRK3 and GRK5, whereby GRK2 is the most abundant isoform (Penn et al 2000). Several studies have demonstrated that one of the strongest stimuli to activate GRK2 is increased sympathetic activity via β-AR stimulation, whereas α-1 AR stimulation appears not to activate GRK2 (Iaccarino et al 1998;Penela et al 2003Penela et al , 2006.…”

Section: Effects On Force-frequency Relationshipmentioning

confidence: 99%

β-adrenoceptor blocker treatment and the cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure

Brodde

2007

Naunyn-Schmied Arch Pharmacol

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Section: Effects On Force-frequency Relationshipmentioning

confidence: 99%

β-adrenoceptor blocker treatment and the cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure

Brodde

2007

Naunyn-Schmied Arch Pharmacol

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“…However, this model seems unlikely to describe the major physiological mechanism because other receptor domains exposed on agonist binding appear to promote GRK -receptor interactions independently of regions that are subsequently phosphorylated [10,45]. Despite the lack of information regarding the initiation of GPCR and GRK interactions, many positive and negative regulators of GRK activity have been identified and reviewed extensively [10,45,46]. Thus, a diverse array of proteins and lipids can regulate GRK activity, either affecting membrane localization or enzymatic activity as a result of GRK phosphorylation by a variety of kinases.…”

Section: Does the Regulation Of Non-visual Grks Provide Clues To Theimentioning

confidence: 99%

Non-visual GRKs: are we seeing the whole picture?

Willets

Challiss

Nahorski

2003

Trends in Pharmacological Sciences

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G-protein-coupled receptor kinases (GRKs) comprise a family of seven mammalian serine/threonine protein kinases that phosphorylate and regulate agonist-occupied or constitutively active G-protein-coupled receptors (GPCRs). Studies of the details and consequences of these mechanisms have focused heavily on the original b-adrenoceptor kinase (b-ARK) family (GRK2 and GRK3) and, in particular, on phosphorylation-dependent recruitment of adaptor proteins such as the b-arrestins. However, recent work has indicated roles for the other, non-visual GRKs (GRK4, GRK5 and GRK6) and has revealed potential phosphorylation-independent regulation of GPCRs by GRK2 and GRK3. In this article, we review this newer information and attempt to put it into context with GRKs as physiological regulators that could be appropriate targets for future pharmacological intervention.G-protein-coupled receptors (GPCRs) constitute a very large family of heptahelical, integral membrane proteins that mediate a wide variety of physiological processes ranging from the transmission of light and odorant signals to the mediation of neurotransmission and hormonal actions [1,2]. GPCRs represent a major target for therapeutic agents, and the continuing identification of orphan GPCRs offers opportunity for future pharmacological and therapeutic development [3].Most GPCRs display a rapid loss of responsiveness in the continuing (or recurring) presence of an agonist or stimulus, and there is now substantial evidence that this process of desensitization, at least in part, is a consequence of ligand-induced phosphorylation of serine and threonine residues located within the C-terminal domain and/or the third intracellular loop of GPCRs. Two families of protein kinases appear to be predominantly involved: the G-protein-coupled receptor kinases (GRKs), which phosphorylate agonist-occupied GPCRs to mediate homologous receptor phosphorylation, and the second messengeractivated kinases, such as cAMP-dependent kinase (PKA) and protein kinase C (PKC), which can phosphorylate both ligand-bound and other inactive GPCRs in a heterologous manner [4,5]. Phosphorylation by GRKs enhances receptor affinity for non-visual b-arrestins 1 and 2 (arrestin2 and arrestin3), which not only sterically suppresses further interaction between the receptor and G proteins, but also initiates clathrin-mediated endocytosis of phosphorylated receptors and can promote the activation of additional signalling pathways by acting as agonist-regulated adaptor scaffolds [6].Other protein kinases have also been implicated in GPCR regulation. For example, evidence has accumulated that casein kinase 1a might bring about agonistmediated phosphorylation of acetylcholine muscarinic M 3 receptors and light-activated rhodopsin [7]. Casein kinase 1a-mediated phosphorylation does not appear to be associated with reduced responsiveness of the M 3 receptor but probably contributes to the activation of extracellular signal-regulated kinases 1 and 2 (ERK1,2) by this receptor [8,9].Although research in this area h...

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“…The NT of GRK2 is thought to mediate receptor recognition and intracellular membrane anchoring. 11 Furthermore, it harbors the RGS domain (regulator of G-protein signaling homology domain), which is thought to be responsible for the regulation of GPCR signaling independent of phosphorylation. 12,13 The CT region of GRK2 contains a pleckstrin homology domain (PH) that contains sites responsible for binding to the bg-subunits of dissociation (that is, activated) G proteins (G bg ), which targets this kinase to the membrane to enhance GPCR phosphorylation.…”

Section: Grk2: a Nodal Culprit In Hf Grk2 And The Cardiomyocytementioning

confidence: 99%

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

et al. 2012

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Heart failure (HF) is a common pathological end point for several cardiac diseases. Despite reasonable achievements in pharmacological, electrophysiological and surgical treatments, prognosis for chronic HF remains poor. Modern therapies are generally symptom oriented and do not currently address specific intracellular molecular signaling abnormalities. Therefore, new and innovative therapeutic approaches are warranted and, ideally, these could at least complement established therapeutic options if not replace them. Gene therapy has potential to serve in this regard in HF as vectors can be directed toward diseased myocytes and directly target intracellular signaling abnormalities. Within this review, we will dissect the adrenergic system contributing to HF development and progression with special emphasis on G-protein-coupled receptor kinase 2 (GRK2). The levels and activity of GRK2 are increased in HF and we and others have demonstrated that this kinase is a major molecular culprit in HF. We will cover the evidence supporting gene therapy directed against myocardial as well as adrenal GRK2 to improve the function and structure of the failing heart and how these strategies may offer complementary and synergistic effects with the existing HF mainstay therapy of b-adrenergic receptor antagonism.

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Regulation of G Protein-Coupled Receptor Kinases

Cited by 196 publications

References 50 publications

β-adrenoceptor blocker treatment and the cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure

β-adrenoceptor blocker treatment and the cardiac β-adrenoceptor-G-protein(s)-adenylyl cyclase system in chronic heart failure

Non-visual GRKs: are we seeing the whole picture?

Targeting GRK2 by gene therapy for heart failure: benefits above β-blockade

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