Spatiotemporal GPCR signaling illuminated by genetically encoded fluorescent biosensors

Kayser, Charlotte; Melkes, Barbora; Derieux, Cécile; Böck, Andreas

doi:10.1016/j.coph.2023.102384

Cited by 11 publications

(3 citation statements)

References 71 publications

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“…In our laboratory, we have previously demonstrated high expression of sAC in the mouse hippocampus, cortex, and HT22 cells (2,26). Additionally, it has been reported that sAC and tmACs can tightly regulate distinct downstream pathways from specific microdomains, leading to the spatiotemporal control of internal cAMP pools (3,(37)(38)(39). Given the observation that cAMP response increases upon UCNs stimulation, we next explored the impact of these two different cAMP sources on the activation of ERK1/2, CREB and the induction of c-Fos mRNA.…”

Section: Tmac and Sac Mediate Erk1/2 Creb And C-fos Activationmentioning

confidence: 96%

Role of canonical and non-canonical cAMP Sources in CRHR2α-dependent Signaling

Armando,

dos Santos Claro,

Fuertes

et al. 2023

Preprint

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Hippocampal neurons exhibit activation of both the conventional transmembrane adenylyl cyclases (tmACs) and the non-canonical soluble adenylyl cyclase (sAC) as sources of cyclic AMP (cAMP). These two cAMP sources play crucial roles in mediating signaling pathways downstream of CRHR1 in neuronal and neuroendocrine contexts. In this study, we investigate the involvement of both cAMP sources in the molecular mechanisms triggered by CRHR2α. Here we provide evidence demonstrating that UCN1 and UCN3 exert a neuritogenic effect on HT22-CRHR2α cells, which is solely dependent on the cAMP pool generated by sAC and PKA activity but independent of ERK1/2 activation. Through the characterization of the effectors implicated in neurite elongation, we found that CREB phosphorylation and c-Fos induction rely on PKA activity and ERK1/2 phosphorylation, underscoring the critical role of signaling pathway regulation. These findings strengthen the concept that localized cAMP microdomains actively participate in the regulation of these signaling processes.

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Section: Tmac and Sac Mediate Erk1/2 Creb And C-fos Activationmentioning

confidence: 96%

Role of canonical and non-canonical cAMP Sources in CRHR2α-dependent Signaling

Armando,

dos Santos Claro,

Fuertes

et al. 2023

Preprint

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“…New assays have been developed to determine microinteractions of receptors with the complete complement of G proteins in a cell (Avet et al, 2022;Inoue et al, 2019;Olsen et al, 2020). The application of pathway-selective BRET biosensors that monitor the engagement and activation of signalling effectors Nanoluciferase-based complementation assays also have been used to provide textured readouts of biased signalling (Laschet et al, 2019), and genetically encoded fluorescent biosensors have been employed to illuminate spatiotemporal biased signalling (Kayser et al, 2023).…”

Section: Identifying and Measuring Biasmentioning

confidence: 99%

“…In fact, it has been shown that the bias of opioid agonists is independent of the rate of interaction of the molecules with the receptor (Pedersen et al, 2020). New techniques are being used to explore this variant in bias; that is, genetically encoded fluorescent biosensors have been employed to illuminate spatiotemporal biased signalling (Kayser et al, 2023).…”

Section: Varying Temporal Differentiation Of Agonist Signals In Cellsmentioning

confidence: 99%

Bias translation: The final frontier?

Kenakin

2024

British J Pharmacology

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Biased signalling is a natural result of GPCR allosteric function and should be expected from any and all synthetic and natural agonists. Therefore, it may be encountered in all agonist discovery projects and must be considered as a beneficial (or possible detrimental) feature of new candidate molecules. While bias is detected easily, the synoptic nature of GPCR signalling makes translation of simple in vitro bias to complex in vivo systems problematic. The practical outcome of this is a difficulty in predicting the therapeutic value of biased signalling due to the failure of translation of identified biased signalling to in vivo agonism. This is discussed in this review as well as some new ways forward to improve this translation process and better exploit this powerful pharmacologic mechanism.

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