scholarly journals Different cAMP sources are critically involved in G protein–coupled receptor CRHR1 signaling

2016 ◽  
Vol 214 (2) ◽  
pp. 181-195 ◽  
Author(s):  
Carolina Inda ◽  
Paula A. dos Santos Claro ◽  
Juan J. Bonfiglio ◽  
Sergio A. Senin ◽  
Giuseppina Maccarrone ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Cyclic Amp ◽  
G Protein ◽  
Adenylyl Cyclases ◽  
Alternative Source ◽  
Soluble Adenylyl Cyclase ◽  
Extracellular Signal Regulated Kinase ◽  
Signaling Mechanisms ◽  
Extracellular Signal ◽  
G Protein Coupled

Corticotropin-releasing hormone receptor 1 (CRHR1) activates G protein–dependent and internalization-dependent signaling mechanisms. Here, we report that the cyclic AMP (cAMP) response of CRHR1 in physiologically relevant scenarios engages separate cAMP sources, involving the atypical soluble adenylyl cyclase (sAC) in addition to transmembrane adenylyl cyclases (tmACs). cAMP produced by tmACs and sAC is required for the acute phase of extracellular signal regulated kinase 1/2 activation triggered by CRH-stimulated CRHR1, but only sAC activity is essential for the sustained internalization-dependent phase. Thus, different cAMP sources are involved in different signaling mechanisms. Examination of the cAMP response revealed that CRH-activated CRHR1 generates cAMP after endocytosis. Characterizing CRHR1 signaling uncovered a specific link between CRH-activated CRHR1, sAC, and endosome-based signaling. We provide evidence of sAC being involved in an endocytosis-dependent cAMP response, strengthening the emerging model of GPCR signaling in which the cAMP response does not occur exclusively at the plasma membrane and introducing the notion of sAC as an alternative source of cAMP.

scholarly journals Adenylyl cyclases (ACs) (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Carmen W. Dessauer ◽  
Rennolds Ostrom ◽  
Roland Seifert ◽  
Val J. Watts
Keyword(s):  
Cyclic Amp ◽  
Adenylyl Cyclase ◽  
G Protein ◽  
Adenylyl Cyclases ◽  
Adenylyl Cyclase Activity ◽  
Α Subunit ◽  
Soluble Adenylyl Cyclase ◽  
Catalytic Domains ◽  
Stimulatory G Protein ◽  
Membrane Spanning

Adenylyl cyclase, E.C. 4.6.1.1, converts ATP to cyclic AMP and pyrophosphate. Mammalian membrane-delimited adenylyl cyclases (nomenclature as approved by the NC-IUPHAR Subcommittee on Adenylyl cyclases [9]) are typically made up of two clusters of six TM domains separating two intracellular, overlapping catalytic domains that are the target for the nonselective activators Gαs (the stimulatory G protein α subunit) and forskolin (except AC9, [21]). adenosine and its derivatives (e.g. 2',5'-dideoxyadenosine), acting through the P-site,are inhibitors of adenylyl cyclase activity [27]. Four families of membranous adenylyl cyclase are distinguishable: calmodulin-stimulated (AC1, AC3 and AC8), Ca2+- and Gβγ-inhibitable (AC5, AC6 and AC9), Gβγ-stimulated and Ca2+-insensitive (AC2, AC4 and AC7), and forskolin-insensitive (AC9) forms. A soluble adenylyl cyclase (AC10) lacks membrane spanning regions and is insensitive to G proteins.It functions as a cytoplasmic bicarbonate (pH-insensitive) sensor [5].

scholarly journals Chemokine Production by G Protein-Coupled Receptor Activation in a Human Mast Cell Line: Roles of Extracellular Signal-Regulated Kinase and NFAT

2000 ◽  
Vol 165 (12) ◽  
pp. 7215-7223 ◽  
Author(s):  
Hydar Ali ◽  
Jasimuddin Ahamed ◽  
Cristina Hernandez-Munain ◽  
Jonathan L. Baron ◽  
Michael S. Krangel ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Line ◽  
G Protein ◽  
Receptor Activation ◽  
Human Mast Cell ◽  
Chemokine Production ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mast Cell Line ◽  
G Protein Coupled

scholarly journals Spatial resolution of cAMP signaling by soluble adenylyl cyclase

2016 ◽  
Vol 214 (2) ◽  
pp. 125-127 ◽  
Author(s):  
Giusi Caldieri ◽  
Sara Sigismund
Keyword(s):  
Plasma Membrane ◽  
Adenylyl Cyclase ◽  
G Protein ◽  
Spatial Resolution ◽  
Camp Signaling ◽  
Receptor Signaling ◽  
Soluble Adenylyl Cyclase ◽  
Spatial Encoding ◽  
Cell Biol ◽  
G Protein Coupled

G protein–coupled receptor signaling starts at the plasma membrane and continues at endosomal stations. In this issue, Inda et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201512075) show that different forms of adenylyl cyclase are activated at the plasma membrane versus endosomes, providing a rationale for the spatial encoding of cAMP signaling.

scholarly journals Multifaceted roles of β-arrestins in the regulation of seven-membrane-spanning receptor trafficking and signalling

2003 ◽  
Vol 375 (3) ◽  
pp. 503-515 ◽  
Author(s):  
Sudha K. SHENOY ◽  
Robert J. LEFKOWITZ
Keyword(s):  
G Protein ◽  
Receptor Internalization ◽  
Adapter Proteins ◽  
Adapter Protein ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Membrane Spanning ◽  
G Protein Coupled ◽  
Adp Ribosylation Factor

β-Arrestins are cytosolic proteins that bind to activated and phosphorylated G-protein-coupled receptors [7MSRs (seven-membrane-spanning receptors)] and uncouple them from G-protein-mediated second messenger signalling pathways. The binding of β-arrestins to 7MSRs also leads to new signals via activation of MAPKs (mitogen-activated protein kinases) such as JNK3 (c-Jun N-terminal kinase 3), ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 MAPKs. By binding to endocytic proteins [clathrin, AP2 (adapter protein 2), NSF (N-ethylmaleimide-sensitive fusion protein) and ARF6 (ADP-ribosylation factor 6)], β-arrestins also serve as adapters to link the receptors to the cellular trafficking machinery. Agonist-promoted ubiquitination of β-arrestins is a prerequisite for their role in receptor internalization, as well as a determinant of the differing trafficking patterns of distinct classes of receptors. Recently, β-arrestins have also been implicated as playing novel roles in cellular chemotaxis and apoptosis. By virtue of their ability to bind, in a stimulus-dependent fashion, to 7MSRs as well as to different classes of cellular proteins, β-arrestins serve as versatile adapter proteins that regulate the signalling and trafficking of the receptors.

scholarly journals Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors

2019 ◽  
Author(s):  
Jeffrey S. Smith ◽  
Thomas F. Pack ◽  
Asuka Inoue ◽  
Claudia Lee ◽  
Xinyu Xiong ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Environmental Signals ◽  
Extracellular Signal Regulated Kinase ◽  
Intracellular Signals ◽  
Extracellular Signal ◽  
Extracellular Stimuli ◽  
Protein Isoform ◽  
Sense And Respond ◽  
G Protein Coupled

SummaryG-protein-coupled receptors (GPCRs) enable cells to sense and respond appropriately to hormonal and environmental signals, and are a target of ~30% of all FDA-approved medications. Canonically, each GPCR couples to distinct Gα proteins, such as Gαs, Gαi, Gαq or Gα12/13, as well as β-arrestins. These transducer proteins translate and integrate extracellular stimuli sensed by GPCRs into intracellular signals through what are broadly considered separable signalling pathways. However, the ability of Gα proteins to directly interact with β-arrestins to integrate signalling has not previously been appreciated. Here we show a novel interaction between Gαi protein family members and β-arrestin. Gαi:β-arrestin complexes were formed by all GPCRs tested, regardless of their canonical G protein isoform coupling, and could bind both GPCRs as well as the extracellular signal-regulated kinase (ERK). This novel paradigm of Gαi:β-arrestin scaffolds enhances our understanding of GPCR signalling.

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