Regulation of G Protein–Coupled Receptors

Penn, Raymond B.; Benovic, Jeffrey L.

doi:10.1002/cphy.cp070107

Cited by 20 publications

(31 citation statements)

References 336 publications

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“…Although our previous studies suggested that the EP2 receptor is the functionally dominant EP isoform in human ASM, expression of low levels of either EP1 or EP3 receptors was suggested by effects of various EP ligands on cAMP accumulation (5). EP1 and EP3 receptors can signal through G q and G i heterotrimeric proteins, and thus could influence adenylyl cyclase activity via PKC- and G βγ -dependent mechanisms (11). Moreover, regulation of EP1/EP3 receptor responsiveness by CT-GFP, KR-GFP, or NT-GFP could indirectly regulate EP2R signaling independent of direct effects of these constructs on the EP2R.…”

Section: Resultsmentioning

confidence: 99%

Endogenous G_s-Coupled Receptors in Smooth Muscle Exhibit Differential Susceptibility to GRK2/3-Mediated Desensitization

et al. 2008

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Although G protein-coupled receptor (GPCR) kinases (GRKs) have been shown to mediate desensitization of numerous GPCRs in studies using cellular expression systems, their function under physiological conditions is less well understood. In the current study, we employed various strategies to assess the effect of inhibiting endogenous GRK2/3 on signaling and function of endogenously expressed Gs-coupled receptors in human airway smooth muscle (ASM) cells. GRK2/3 inhibition by expression of a Gβγ sequestrant, a GRK2/3 dominant-negative mutant, or siRNA-mediated knockdown increased intracellular cAMP accumulation mediated via β-agonist stimulation of the beta-2-adrenergic receptor (β2AR). Conversely, neither 5′-(N-ethylcarboxamido)-adenosine (NECA; activating the A2b adenosine receptor) nor prostaglandin E2 (PGE2; activating EP2 or EP4 receptors)-stimulated cAMP was significantly increased by GRK2/3 inhibition. Selective knockdown using siRNA suggested the majority of PGE2-stimulated cAMP in ASM was mediated by the EP2 receptor. Although a minor role for EP3 receptors in influencing PGE2-mediated cAMP was determined, the GRK2/3-resistant nature of EP2 receptor signaling in ASM was confirmed using the EP2-selective agonist butaprost. Somewhat surprisingly, GRK2/3 inhibition did not augment the inhibitory effect of the β-agonist on mitogen-stimulated increases in ASM growth. These findings demonstrate that with respect to Gs-coupled receptors in ASM, GRK2/3 selectively attenuates β2AR signaling, yet relief of GRK2/3-dependent β2AR desensitization does not influence at least one important physiological function of the receptor.

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Section: Resultsmentioning

confidence: 99%

Endogenous G_s-Coupled Receptors in Smooth Muscle Exhibit Differential Susceptibility to GRK2/3-Mediated Desensitization

et al. 2008

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“…β-Agonists mediate their effect primarily by increasing cAMP concentration through activation of β 2 -adrenergic receptor-adenylyl cyclase pathway. Several mediators of inflammation and therapies such as β-agonists themselves can cause alterations in β 2 -adrenergic receptor responsiveness in a time-dependent and cell-specific manner (Penn and Benovic 1998). The loss of prophylactic bronchoprotection and deterioration of asthma control observed in patients who use β-agonists regularly may be due to agonist-specific desensitization of the receptor.…”

Section: Hspb6 and Pathologic Processesmentioning

confidence: 99%

The small heat shock protein, HSPB6, in muscle function and disease

Dreiza

Komalavilas

Furnish

et al. 2010

Cell Stress and Chaperones

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The small heat shock protein, HSPB6, is a 17-kDa protein that belongs to the small heat shock protein family. HSPB6 was identified in the mid-1990s when it was recognized as a by-product of the purification of HSPB1 and HSPB5. HSPB6 is highly and constitutively expressed in smooth, cardiac, and skeletal muscle and plays a role in muscle function. This review will focus on the physiologic and biochemical properties of HSPB6 in smooth, cardiac, and skeletal muscle; the putative mechanisms of action; and therapeutic implications.

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“…1), which also serves as an example of prototypical heterotrimeric G protein signalling. Early studies by Gilman, Lefkowitz, Birnbaum, Bourne, Perkins, and others (reviewed in (Penn and Benovic, 1998)) characterize transmembrane signalling involving GPCR (β 2 AR), heterotrimeric G protein (Gs for the β 2 AR) and an effector (adenylyl cyclase downstream of β 2 AR-Gs). Adenylyl cyclase mediates the hydrolysis of ATP into cAMP, which in turn activates the cAMP-dependent protein kinase (aka PKA (Protein kinase A)).…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

β2 Agonists

Billington

Penn

Hall

2016

Handbook of Experimental Pharmacology

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146

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History suggests β agonists, the cognate ligand of the β2adrenoceptor, have been used as bronchodilators for around 5000 years, and β agonists remain today the frontline treatment for asthma and Chronic Obstructive Pulmonary Disease (COPD). The β agonists used clinically today are the products of significant expenditure and over a hundred year's intensive research aimed at minimising side effects and enhancing therapeutic usefulness. The respiratory physician now has a therapeutic toolbox of long acting β agonists to prophylactically manage bronchoconstriction, and short acting β agonists to relieve acute exacerbations. Despite constituting the cornerstone of asthma and COPD therapy, these drugs are not perfect; significant safety issues have led to a black box warning advising that long acting β agonists should not be used alone in patients with asthma. In addition there are a significant proportion of patients whose asthma remains uncontrolled. In this chapter we discuss the evolution of β agonist use and how the understanding of β agonist actions on their principal target tissue, airway smooth muscle, has led to greater understanding of how these drugs can be further modified and improved in the future. Research into the genetics of the β2adrenoceptor will also be discussed, as will the implications of individual DNA profiles on the clinical outcomes of β agonist use (pharmacogenetics). Finally we comment on what the future may hold for the use of β agonists in respiratory disease.

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Regulation of G Protein–Coupled Receptors

Cited by 20 publications

References 336 publications

Endogenous G_s-Coupled Receptors in Smooth Muscle Exhibit Differential Susceptibility to GRK2/3-Mediated Desensitization

Endogenous G_s-Coupled Receptors in Smooth Muscle Exhibit Differential Susceptibility to GRK2/3-Mediated Desensitization

The small heat shock protein, HSPB6, in muscle function and disease

β2 Agonists

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Regulation of G Protein–Coupled Receptors

Cited by 20 publications

References 336 publications

Endogenous Gs-Coupled Receptors in Smooth Muscle Exhibit Differential Susceptibility to GRK2/3-Mediated Desensitization

Endogenous Gs-Coupled Receptors in Smooth Muscle Exhibit Differential Susceptibility to GRK2/3-Mediated Desensitization

The small heat shock protein, HSPB6, in muscle function and disease

β2 Agonists

Contact Info

Product

Resources

About

Endogenous G_s-Coupled Receptors in Smooth Muscle Exhibit Differential Susceptibility to GRK2/3-Mediated Desensitization

Endogenous G_s-Coupled Receptors in Smooth Muscle Exhibit Differential Susceptibility to GRK2/3-Mediated Desensitization