G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function

Mohan, Maradumane L; Vasudevan, Neelakantan T; Gupta, Mohak; Martelli, Elizabeth E; Prasad, Sathyamangla V. Naga

doi:10.2174/1874467211205030004

Cited by 33 publications

(30 citation statements)

References 125 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This process understandably guards cells against excessive stimulation, while resensitization protects cells against prolonged hormone resistance [1]. Receptor inactivation proceeds at the cell surface but is commonly followed by endocytosis [2].…”

Section: The Classical Viewmentioning

confidence: 99%

GPCR Signaling and Trafficking: The Long and Short of It

Pavlos

Friedman

2017

Trends in Endocrinology & Metabolism

166

121

View full text Add to dashboard Cite

Emerging findings disclose unexpected components of G protein-coupled receptor (GPCR) signaling and cell biology. Select GPCRs exhibit classical signaling that is restricted to cell membranes and newly described persistent signaling that depends on internalization of the GPCR bound to β-arrestins. Termination of non-canonical endosomal signaling requires intraluminal acidification and sophisticated protein trafficking machineries. Recent studies reveal the structural determinants of the trafficking chaperones. This review summarizes advances in GPCR signaling and trafficking with a focus on the parathyroid hormone receptor as prototype, and the actin-SNX27-retromer tubule complex, an endosomal sorting hub responsible for recycling and preservation of cell surface receptors. The findings are integrated into a model of PTHR trafficking with implications for signal transduction, bone growth, and mineral-ion metabolism.

show abstract

Section: The Classical Viewmentioning

confidence: 99%

GPCR Signaling and Trafficking: The Long and Short of It

Pavlos

Friedman

2017

Trends in Endocrinology & Metabolism

166

121

View full text Add to dashboard Cite

show abstract

“…This mechanism was initially thought to be involved in regulating the density of the GPCR either by resensitization or by down-regulation [5, 6]. Lately, it has evolved as a major mechanism involved in a variety of physiological responses, such as MAP kinase activation and in sustained signaling by the internalized GPCR to generate unique physiological responses that are different from plasma membrane delimited signaling [7].…”

Section: Introductionmentioning

confidence: 99%

Barcoding of GPCR trafficking and signaling through the various trafficking roadmaps by compartmentalized signaling networks

Bahouth

Nooh

2017

Cellular Signalling

View full text Add to dashboard Cite

Proper signaling by G protein coupled receptors (GPCR) is dependent on the specific repertoire of transducing, enzymatic and regulatory kinases and phosphatases that shape its signaling output. Activation and signaling of the GPCR through its cognate G protein is impacted by G protein-coupled receptor kinase (GRK)-imprinted “barcodes” that recruit ß-arrestins to regulate subsequent desensitization, biased signaling and endocytosis of the GPCR. The outcome of agonist-internalized GPCR in endosomes is also regulated by sequence motifs or “barcodes” within the GPCR that mediate its recycling to the plasma membrane or retention and eventual degradation as well as its subsequent signaling in endosomes. Given the vast number of diverse sequences in GPCR, several trafficking mechanisms for endosomal GPCR have been described. The majority of recycling GPCR, are sorted out of endosomes in a “sequence-dependent pathway” anchored around a type-1 PDZ-binding module found in their C-tails. For a subset of these GPCR, a second “barcode” imprinted onto specific GPCR serine/threonine residues by compartmentalized kinase networks was required for their efficient recycling through the “sequence-dependent pathway”. Mutating the serine/threonine residues involved, produced dramatic effects on GPCR trafficking, indicating that they played a major role in setting the trafficking itinerary of these GPCR. While endosomal SNX27, retromer/WASH complexes and actin were required for efficient sorting and budding of all these GPCR, additional proteins were required for GPCR sorting via the second “barcode”. Here we will review recent developments in GPCR trafficking in general and the human ß1-adrenergic receptor in particular across the various trafficking roadmaps. In addition, we will discuss the role of GPCR trafficking in regulating endosomal GPCR signaling, which promote biochemical and physiological effects that are distinct from those generated by the GPCR signal transduction pathway in membranes.

show abstract

“…One mechanism involves receptor complex desensitization, for switching off receptor activation at the plasma membrane. However, it should be noted that internalized receptor-effector complexes can engage in signal propagation and that receptor recycling and synthesis is critical for reactivation of signal transmission and oscillations [14,[23][24][25]. Another way to limit the diffusion or abundance of cAMP is achieved by the presence and activation of phosphodiesterases (PDEs) [26][27][28][29][30].…”

Section: Camp Mobilizationmentioning

confidence: 99%

Hedgehog and Gpr161: Regulating cAMP Signaling in the Primary Cilium

Tschaikner

Enzler

Torres‐Quesada

et al. 2020

Cells

View full text Add to dashboard Cite

Compartmentalization of diverse types of signaling molecules contributes to the precise coordination of signal propagation. The primary cilium fulfills this function by acting as a spatiotemporally confined sensory signaling platform. For the integrity of ciliary signaling, it is mandatory that the ciliary signaling pathways are constantly attuned by alterations in both oscillating small molecules and the presence or absence of their sensor/effector proteins. In this context, ciliary G protein-coupled receptor (GPCR) pathways participate in coordinating the mobilization of the diffusible second messenger molecule 3′,5′-cyclic adenosine monophosphate (cAMP). cAMP fluxes in the cilium are primarily sensed by protein kinase A (PKA) complexes, which are essential for the basal repression of Hedgehog (Hh) signaling. Here, we describe the dynamic properties of underlying signaling circuits, as well as strategies for second messenger compartmentalization. As an example, we summarize how receptor-guided cAMP-effector pathways control the off state of Hh signaling. We discuss the evidence that a macromolecular, ciliary-localized signaling complex, composed of the orphan GPCR Gpr161 and type I PKA holoenzymes, is involved in antagonizing Hh functions. Finally, we outline how ciliary cAMP-linked receptor pathways and cAMP-sensing signalosomes may become targets for more efficient combinatory therapy approaches to counteract dysregulation of Hh signaling.

show abstract

G-Protein Coupled Receptor Resensitization - Appreciating the Balancing Act of Receptor Function

Cited by 33 publications

References 125 publications

GPCR Signaling and Trafficking: The Long and Short of It

GPCR Signaling and Trafficking: The Long and Short of It

Barcoding of GPCR trafficking and signaling through the various trafficking roadmaps by compartmentalized signaling networks

Hedgehog and Gpr161: Regulating cAMP Signaling in the Primary Cilium

Contact Info

Product

Resources

About