Compartmentalized cAMP Generation by Engineered Photoactivated Adenylyl Cyclases

O’Banion, Colin P.; Vickerman, Brianna M.; Haar, Lauren; Lawrence, David S.

doi:10.1016/j.chembiol.2019.07.004

Cited by 18 publications

(14 citation statements)

References 51 publications

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“…However, additional studies will be required to fully elucidate the mechanistic basis for differential control of AC9 trafficking, and to delineate physiological inputs into regulated AC trafficking more broadly. The physiological significance of isoform-specific AC trafficking also remains to be determined, but we note that there is already significant evidence that cAMP produced internally can mediate different downstream signaling effects relative to cAMP produced from the plasma membrane ( O'Banion et al, 2019 ; Tsvetanova and von Zastrow, 2014 ).…”

Section: Discussionmentioning

confidence: 94%

G protein-regulated endocytic trafficking of adenylyl cyclase type 9

Lazar

Irannejad

Baldwin

et al. 2020

eLife

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GPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report selective trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes while adenylyl cyclase type 1 (AC1) remains in the plasma membrane, and stimulation of AC9 trafficking by ligand-induced activation of Gs-coupled GPCRs. AC9 transits a similar, dynamin-dependent early endocytic pathway as ligand-activated GPCRs. However, unlike GPCR traffic control which requires β-arrestin but not Gs, AC9 traffic control requires Gs but not β-arrestin. We also show that AC9, but not AC1, mediates cAMP production stimulated by endogenous receptor activation in endosomes. These results reveal dynamic and isoform-specific trafficking of adenylyl cyclase in the endocytic network, and a discrete role of a heterotrimeric G protein in regulating the subcellular distribution of a relevant effector.

show abstract

Section: Discussionmentioning

confidence: 94%

G protein-regulated endocytic trafficking of adenylyl cyclase type 9

Lazar

Irannejad

Baldwin

et al. 2020

eLife

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show abstract

“…However, additional study will be required to define the mechanistic basis for differential control of AC9, and to delineate physiological input(s) regulating AC trafficking more broadly. The functional significance of distinct AC traffic control also remains to be further investigated, but we note that there is already significant evidence that cAMP production internally in the cytoplasm can produce different downstream effects relative to production from the plasma membrane (O’Banion et al, 2019; Tsvetanova and von Zastrow, 2014).…”

Section: Discussionmentioning

confidence: 94%

G protein-regulated endocytic trafficking of adenylyl cyclase type 9

Lazar

Irannejad

Baldwin³

et al. 2020

Preprint

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SummaryGPCRs are increasingly recognized to initiate signaling via heterotrimeric G proteins as they move through the endocytic network, but little is known about how relevant G protein effectors are localized. Here we report dynamic trafficking of adenylyl cyclase type 9 (AC9) from the plasma membrane to endosomes, while adenylyl cyclase type 1 (AC1) remains in the plasma membrane, and stimulation of AC9 trafficking by ligand-induced activation of Gs-coupled GPCRs or Gs. AC9 transits a similar dynamin-dependent early endocytic pathway as activated GPCRs but, in contrast to GPCR trafficking which is regulated by β-arrestin but not Gs, AC9 trafficking is regulated by Gs but not β-arrestin. We also show that AC9, but not AC1, contributes to cAMP production from endosomes. These results reveal dynamic and isoform-specific trafficking of adenylyl cyclase in the endocytic network, and a discrete role of a heterotrimeric G protein in controlling subcellular location of a relevant effector.

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“…Endosomal activation has only a small effect on global cAMP elevation but is essential for efficient downstream signaling to cAMP-dependent gene transcription. Further, signaling to the nucleus has been explicitly demonstrated to occur as a consequence of moving the subcellular location of cAMP production rather than changing the total amount of cAMP produced 17 , 18 .…”

Section: Introductionmentioning

confidence: 99%

Spatial decoding of endosomal cAMP signals by a metastable cytoplasmic PKA network

et al. 2021

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GPCR-regulated cAMP production from endosomes can specify signaling to the nucleus by moving the source of cAMP without changing its amount. How this is possible remains unknown because cAMP gradients dissipate over the nanoscale whereas endosomes typically localize microns from the nucleus. We show that the key location-dependent step for endosome-encoded transcriptional control is nuclear entry of cAMP-dependent protein kinase (PKA) catalytic subunits. These are sourced from punctate accumulations of PKA holoenzyme that are densely distributed in the cytoplasm and titrated by global cAMP into a discrete metastable state, in which catalytic subunits are bound but dynamically exchange. Mobile endosomes containing activated receptors collide with the metastable PKA puncta and pause in close contact. We propose that these properties enable cytoplasmic PKA to act collectively like a semiconductor, converting nanoscale cAMP gradients generated from endosomes into microscale elevations of free catalytic subunit to direct downstream signaling.

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Compartmentalized cAMP Generation by Engineered Photoactivated Adenylyl Cyclases

Abstract: Highlights d Design of engineered organelle-targeted optogenetic adenylate cyclases d Assessment of organelle-based cAMP-induced protein kinase activity d Identification of phosphodiesterases that modulate cAMPsignaling activity

Cited by 18 publications

References 51 publications

G protein-regulated endocytic trafficking of adenylyl cyclase type 9

G protein-regulated endocytic trafficking of adenylyl cyclase type 9

G protein-regulated endocytic trafficking of adenylyl cyclase type 9

Spatial decoding of endosomal cAMP signals by a metastable cytoplasmic PKA network

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