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Article ; Online: Lipophagy at a glance.

Schott, Micah B / Rozeveld, Cody N / Weller, Shaun G / McNiven, Mark A

2022 Volume 135, Issue 5

Abstract: Lipophagy is a central cellular process for providing the cell with a readily utilized, high energy source of neutral lipids. Since its discovery over a decade ago, we are just starting to understand the molecular components that drive lipophagy, how it ... ...

Abstract	Lipophagy is a central cellular process for providing the cell with a readily utilized, high energy source of neutral lipids. Since its discovery over a decade ago, we are just starting to understand the molecular components that drive lipophagy, how it is activated in response to nutrient availability, and its potential as a therapeutic target in disease. In this Cell Science at a Glance article and the accompanying poster, we first provide a brief overview of the different structural and enzymatic proteins that comprise the lipid droplet (LD) proteome and reside within the limiting phospholipid monolayer of this complex organelle. We then highlight key players in the catabolic breakdown of LDs during the functionally linked lipolysis and lipophagy processes. Finally, we discuss what is currently known about macro- and micro-lipophagy based on findings in yeast, mammalian and other model systems, and how impairment of these important functions can lead to disease states.
MeSH term(s)	Animals ; Autophagy/physiology ; Lipid Droplets/metabolism ; Lipid Metabolism/physiology ; Lipolysis ; Mammals/metabolism ; Phospholipids/metabolism ; Proteins/metabolism ; Saccharomyces cerevisiae/metabolism
Chemical Substances	Phospholipids ; Proteins
Language	English
Publishing date	2022-03-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.259402
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Article ; Online: Luteal Lipid Droplets: A Novel Platform for Steroid Synthesis.

Plewes, Michele R / Talbott, Heather A / Saviola, Anthony J / Woods, Nicholas T / Schott, Micah B / Davis, John S

Endocrinology

2023 Volume 164, Issue 9

Abstract: Progesterone is an essential steroid hormone that is required to initiate and maintain pregnancy in mammals and serves as a metabolic intermediate in the synthesis of endogenously produced steroids, including sex hormones and corticosteroids. ... ...

Abstract	Progesterone is an essential steroid hormone that is required to initiate and maintain pregnancy in mammals and serves as a metabolic intermediate in the synthesis of endogenously produced steroids, including sex hormones and corticosteroids. Steroidogenic luteal cells of the corpus luteum have the tremendous capacity to synthesize progesterone. These specialized cells are highly enriched with lipid droplets that store lipid substrate, which can be used for the synthesis of steroids. We recently reported that hormone-stimulated progesterone synthesis by luteal cells requires protein kinase A-dependent mobilization of cholesterol substrate from lipid droplets to mitochondria. We hypothesize that luteal lipid droplets are enriched with steroidogenic enzymes and facilitate the synthesis of steroids in the corpus luteum. In the present study, we analyzed the lipid droplet proteome, conducted the first proteomic analysis of lipid droplets under acute cyclic adenosine monophosphate (cAMP)-stimulated conditions, and determined how specific lipid droplet proteins affect steroidogenesis. Steroidogenic enzymes, cytochrome P450 family 11 subfamily A member 1 and 3 beta-hydroxysteroid dehydrogenase (HSD3B), were highly abundant on lipid droplets of the bovine corpus luteum. High-resolution confocal microscopy confirmed the presence of active HSD3B on the surface of luteal lipid droplets. We report that luteal lipid droplets have the capacity to synthesize progesterone from pregnenolone. Lastly, we analyzed the lipid droplet proteome following acute stimulation with cAMP analog, 8-Br-cAMP, and report increased association of HSD3B with luteal lipid droplets following stimulation. These findings provide novel insights into the role of luteal lipid droplets in steroid synthesis.
MeSH term(s)	Pregnancy ; Female ; Cattle ; Animals ; Progesterone/metabolism ; Lipid Droplets/metabolism ; Proteome/metabolism ; Proteomics ; Corpus Luteum/metabolism ; Steroids ; Hormones/metabolism ; Mammals/metabolism
Chemical Substances	Progesterone (4G7DS2Q64Y) ; Proteome ; Steroids ; Hormones
Language	English
Publishing date	2023-08-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	427856-2
ISSN	1945-7170 ; 0013-7227
ISSN (online)	1945-7170
ISSN	0013-7227
DOI	10.1210/endocr/bqad124
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Article ; Online: Lipid Droplet Contacts With Autophagosomes, Lysosomes, and Other Degradative Vesicles.

Drizyte-Miller, Kristina / Schott, Micah B / McNiven, Mark A

Contact (Thousand Oaks (Ventura County, Calif.))

2020 Volume 3, Page(s) 1–13

Abstract: Lipid droplets (LDs) are dynamic fat-storage organelles that interact readily with numerous cellular structures and organelles. A prominent LD contact site is with degradative vesicles such as autophagosomes, lysosomes, autolysosomes, and late endosomes. ...

Abstract	Lipid droplets (LDs) are dynamic fat-storage organelles that interact readily with numerous cellular structures and organelles. A prominent LD contact site is with degradative vesicles such as autophagosomes, lysosomes, autolysosomes, and late endosomes. These contacts support lipid catabolism through the selective autophagy of LDs (i.e., lipophagy) or the recruitment of cytosolic lipases to the LD surface (i.e., lipolysis). However, LD-autophagosome contacts serve additional functions beyond lipid catabolism, including the supply of lipids for autophagosome biogenesis. In this review, we discuss the molecular mediators of LD contacts with autophagosomes and other degradative organelles as well as the diverse cellular functions of these contact sites in health and disease.
Language	English
Publishing date	2020-03-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2964312-0
ISSN	2515-2564 ; 2515-2564
ISSN (online)	2515-2564
ISSN	2515-2564
DOI	10.1177/2515256420910892
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Article ; Online: The small GTPase Rab32 resides on lysosomes to regulate mTORC1 signaling.

Drizyte-Miller, Kristina / Chen, Jing / Cao, Hong / Schott, Micah B / McNiven, Mark A

Journal of cell science

2020 Volume 133, Issue 11

Abstract: Epithelial cells, such as liver-resident hepatocytes, rely heavily on the Rab family of small GTPases to perform membrane trafficking events that dictate cell physiology and metabolism. Not surprisingly, disruption of several Rab proteins can manifest in ...

Abstract	Epithelial cells, such as liver-resident hepatocytes, rely heavily on the Rab family of small GTPases to perform membrane trafficking events that dictate cell physiology and metabolism. Not surprisingly, disruption of several Rab proteins can manifest in metabolic diseases or cancer. Rab32 is expressed in many secretory epithelial cells but its role in cellular metabolism is virtually unknown. In this study, we find that Rab32 associates with lysosomes and regulates proliferation and cell size of Hep3B hepatoma and HeLa cells. Specifically, we identify that Rab32 supports the mechanistic target of rapamycin complex 1 (mTORC1) signaling under basal and amino acid-stimulated conditions. Consistent with inhibited mTORC1, an increase in nuclear TFEB localization and lysosome biogenesis is also observed in Rab32-depleted cells. Finally, we find that Rab32 interacts with mTOR kinase, and that loss of Rab32 reduces the association of mTOR and mTORC1 pathway proteins with lysosomes, suggesting that Rab32 regulates lysosomal mTOR trafficking. In summary, these findings suggest that Rab32 functions as a novel regulator of cellular metabolism through supporting mTORC1 signaling.This article has an associated First Person interview with the first author of the paper.
MeSH term(s)	HeLa Cells ; Humans ; Lysosomes/metabolism ; Mechanistic Target of Rapamycin Complex 1/genetics ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Monomeric GTP-Binding Proteins/genetics ; Monomeric GTP-Binding Proteins/metabolism ; Signal Transduction ; rab GTP-Binding Proteins
Chemical Substances	Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; Rab32 protein, human (EC 3.6.1.-) ; Monomeric GTP-Binding Proteins (EC 3.6.5.2) ; rab GTP-Binding Proteins (EC 3.6.5.2)
Language	English
Publishing date	2020-06-11
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2993-2
ISSN	1477-9137 ; 0021-9533
ISSN (online)	1477-9137
ISSN	0021-9533
DOI	10.1242/jcs.236661
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Article ; Online: Hydroxysteroid 17β-dehydrogenase 11 accumulation on lipid droplets promotes ethanol-induced cellular steatosis.

Thomes, Paul G / Strupp, Michael S / Donohue, Terence M / Kubik, Jacy L / Sweeney, Sarah / Mahmud, R / Schott, Micah B / Schulze, Ryan J / McNiven, Mark A / Casey, Carol A

The Journal of biological chemistry

2023 Volume 299, Issue 4, Page(s) 103071

Abstract: Lipid droplets (LDs) are fat-storing organelles enclosed by a phospholipid monolayer, which harbors membrane-associated proteins that regulate distinct LD functions. LD proteins are degraded by the ubiquitin-proteasome system (UPS) and/or by lysosomes. ... ...

Abstract	Lipid droplets (LDs) are fat-storing organelles enclosed by a phospholipid monolayer, which harbors membrane-associated proteins that regulate distinct LD functions. LD proteins are degraded by the ubiquitin-proteasome system (UPS) and/or by lysosomes. Because chronic ethanol (EtOH) consumption diminishes the hepatic functions of the UPS and lysosomes, we hypothesized that continuous EtOH consumption slows the breakdown of lipogenic LD proteins targeted for degradation, thereby causing LD accumulation. Here, we report that LDs from livers of EtOH-fed rats exhibited higher levels of polyubiquitylated-proteins, linked at either lysine 48 (directed to proteasome) or lysine 63 (directed to lysosomes) than LDs from pair-fed control rats. MS proteomics of LD proteins, immunoprecipitated with UB remnant motif antibody (K-ε-GG), identified 75 potential UB proteins, of which 20 were altered by chronic EtOH administration. Among these, hydroxysteroid 17β-dehydrogenase 11 (HSD17β11) was prominent. Immunoblot analyses of LD fractions revealed that EtOH administration enriched HSD17β11 localization to LDs. When we overexpressed HSD17β11 in EtOH-metabolizing VA-13 cells, the steroid dehydrogenase 11 became principally localized to LDs, resulting in elevated cellular triglycerides (TGs). Ethanol exposure augmented cellular TG, while HSD17β11 siRNA decreased both control and EtOH-induced TG accumulation. Remarkably, HSD17β11 overexpression lowered the LD localization of adipose triglyceride lipase. EtOH exposure further reduced this localization. Reactivation of proteasome activity in VA-13 cells blocked the EtOH-induced rises in both HSD17β11 and TGs. Our findings indicate that EtOH exposure blocks HSD17β11 degradation by inhibiting the UPS, thereby stabilizing HSD17β11 on LD membranes, to prevent lipolysis by adipose triglyceride lipase and promote cellular LD accumulation.
MeSH term(s)	Animals ; Rats ; Ethanol/pharmacology ; Ethanol/metabolism ; Fatty Liver/metabolism ; Lipase/genetics ; Lipid Droplets/metabolism ; Lipid Metabolism ; Lysine/metabolism ; Proteasome Endopeptidase Complex/metabolism ; 17-Hydroxysteroid Dehydrogenases/metabolism
Chemical Substances	Ethanol (3K9958V90M) ; Lipase (EC 3.1.1.3) ; Lysine (K3Z4F929H6) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; 17-Hydroxysteroid Dehydrogenases (EC 1.1.-)
Language	English
Publishing date	2023-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.103071
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Article ; Online: Receptor-mediated Ca2+ and PKC signaling triggers the loss of cortical PKA compartmentalization through the redistribution of gravin.

Schott, Micah B / Grove, Bryon

Cellular signalling

2013 Volume 25, Issue 11, Page(s) 2125–2135

Abstract: A-Kinase Anchoring Proteins (AKAPs) direct the flow of cellular information by positioning multiprotein signaling complexes into proximity with effector proteins. However, certain AKAPs are not stationary but can undergo spatiotemporal redistribution in ... ...

Abstract	A-Kinase Anchoring Proteins (AKAPs) direct the flow of cellular information by positioning multiprotein signaling complexes into proximity with effector proteins. However, certain AKAPs are not stationary but can undergo spatiotemporal redistribution in response to stimuli. Gravin, a 300kD AKAP that intersects with a diverse signaling array, is localized to the plasma membrane but has been shown to translocate to the cytosol following the elevation of intracellular calcium ([Ca(2+)]i). Despite the potential for gravin redistribution to impact multiple signaling pathways, the dynamics of this event remain poorly understood. In this study, quantitative microscopy of cells expressing gravin-EGFP revealed that Ca(2+) elevation caused the complete translocation of gravin from the cell cortex to the cytosol in as little as 60s of treatment with ionomycin or thapsigargin. In addition, receptor mediated signaling was also shown to cause gravin redistribution following ATP treatment, and this event required both [Ca(2+)]i elevation and PKC activation. To understand the mechanism for Ca(2+) mediated gravin dynamics, deletion of calmodulin-binding domains revealed that a fourth putative calmodulin binding domain called CB4 (a.a. 670-694) is critical for targeting gravin to the cell cortex despite its location downstream of gravin's membrane-targeting domains, which include an N-terminal myristoylation site and three polybasic domains. Finally, confocal microscopy of cells co-transfected with gravin-EYFP and PKA RII-ECFP revealed that gravin redistribution mediated by ionomycin, thapsigargin, and ATP each triggered the gravin-dependent loss of PKA localized at the cell cortex. Our results support the hypothesis that gravin redistribution regulates cross-talk between PKA-dependent signaling and receptor-mediated events involving Ca(2+) and PKC.
MeSH term(s)	A Kinase Anchor Proteins/genetics ; A Kinase Anchor Proteins/metabolism ; Adenosine Triphosphate/metabolism ; Adenosine Triphosphate/pharmacology ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Calcium/metabolism ; Calcium Ionophores/pharmacology ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line, Tumor ; Cell Membrane/drug effects ; Cell Membrane/metabolism ; Cyclic AMP-Dependent Protein Kinases/genetics ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cytosol/drug effects ; Cytosol/metabolism ; Enzyme Inhibitors/pharmacology ; Gene Expression Regulation ; Genes, Reporter ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Humans ; Ionomycin/pharmacology ; Luminescent Proteins/genetics ; Luminescent Proteins/metabolism ; Protein Kinase C/genetics ; Protein Kinase C/metabolism ; Protein Structure, Tertiary ; Protein Transport ; Signal Transduction ; Thapsigargin/pharmacology
Chemical Substances	A Kinase Anchor Proteins ; AKAP12 protein, human ; Bacterial Proteins ; Calcium Ionophores ; Cell Cycle Proteins ; Enzyme Inhibitors ; Luminescent Proteins ; enhanced green fluorescent protein ; yellow fluorescent protein, Bacteria ; Green Fluorescent Proteins (147336-22-9) ; Ionomycin (56092-81-0) ; Thapsigargin (67526-95-8) ; Adenosine Triphosphate (8L70Q75FXE) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Protein Kinase C (EC 2.7.11.13) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2013-07-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2013.07.004
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Article ; Online: The cell biology of the hepatocyte: A membrane trafficking machine.

Schulze, Ryan J / Schott, Micah B / Casey, Carol A / Tuma, Pamela L / McNiven, Mark A

The Journal of cell biology

2019 Volume 218, Issue 7, Page(s) 2096–2112

Abstract: The liver performs numerous vital functions, including the detoxification of blood before access to the brain while simultaneously secreting and internalizing scores of proteins and lipids to maintain appropriate blood chemistry. Furthermore, the liver ... ...

Abstract	The liver performs numerous vital functions, including the detoxification of blood before access to the brain while simultaneously secreting and internalizing scores of proteins and lipids to maintain appropriate blood chemistry. Furthermore, the liver also synthesizes and secretes bile to enable the digestion of food. These diverse attributes are all performed by hepatocytes, the parenchymal cells of the liver. As predicted, these cells possess a remarkably well-developed and complex membrane trafficking machinery that is dedicated to moving specific cargos to their correct cellular locations. Importantly, while most epithelial cells secrete nascent proteins directionally toward a single lumen, the hepatocyte secretes both proteins and bile concomitantly at its basolateral and apical domains, respectively. In this
MeSH term(s)	Animals ; Cell Membrane/genetics ; Cell Membrane/metabolism ; Cell Movement/genetics ; Hepatocytes/metabolism ; Humans ; Liver/metabolism ; Membrane Transport Proteins/chemistry ; Membrane Transport Proteins/genetics ; Parenchymal Tissue/metabolism ; Protein Transport/genetics
Chemical Substances	Membrane Transport Proteins
Language	English
Publishing date	2019-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.201903090
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Article: Receptor-mediated Ca2+ and PKC signaling triggers the loss of cortical PKA compartmentalization through the redistribution of gravin

Schott, Micah B / Grove, Bryon

Cellular signalling. 2013 Nov., v. 25, no. 11

2013

Abstract	A-Kinase Anchoring Proteins (AKAPs) direct the flow of cellular information by positioning multiprotein signaling complexes into proximity with effector proteins. However, certain AKAPs are not stationary but can undergo spatiotemporal redistribution in response to stimuli. Gravin, a 300kD AKAP that intersects with a diverse signaling array, is localized to the plasma membrane but has been shown to translocate to the cytosol following the elevation of intracellular calcium ([Ca2+]i). Despite the potential for gravin redistribution to impact multiple signaling pathways, the dynamics of this event remain poorly understood. In this study, quantitative microscopy of cells expressing gravin–EGFP revealed that Ca2+ elevation caused the complete translocation of gravin from the cell cortex to the cytosol in as little as 60s of treatment with ionomycin or thapsigargin. In addition, receptor mediated signaling was also shown to cause gravin redistribution following ATP treatment, and this event required both [Ca2+]i elevation and PKC activation. To understand the mechanism for Ca2+ mediated gravin dynamics, deletion of calmodulin-binding domains revealed that a fourth putative calmodulin binding domain called CB4 (a.a. 670–694) is critical for targeting gravin to the cell cortex despite its location downstream of gravin's membrane-targeting domains, which include an N-terminal myristoylation site and three polybasic domains. Finally, confocal microscopy of cells co-transfected with gravin–EYFP and PKA RII–ECFP revealed that gravin redistribution mediated by ionomycin, thapsigargin, and ATP each triggered the gravin-dependent loss of PKA localized at the cell cortex. Our results support the hypothesis that gravin redistribution regulates cross-talk between PKA-dependent signaling and receptor-mediated events involving Ca2+ and PKC.
Keywords	adenosine triphosphate ; cAMP-dependent protein kinase ; calcium ; calmodulin ; confocal microscopy ; cortex ; cytosol ; myristoylation ; plasma membrane ; protein kinase C ; signal transduction
Language	English
Dates of publication	2013-11
Size	p. 2125-2135.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	1002702-6
ISSN	0898-6568
ISSN	0898-6568
DOI	10.1016/j.cellsig.2013.07.004
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Direct lysosome-based autophagy of lipid droplets in hepatocytes.

Schulze, Ryan J / Krueger, Eugene W / Weller, Shaun G / Johnson, Katherine M / Casey, Carol A / Schott, Micah B / McNiven, Mark A

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 51, Page(s) 32443–32452

Abstract: Hepatocytes metabolize energy-rich cytoplasmic lipid droplets (LDs) in the lysosome-directed process of autophagy. An organelle-selective form of this process (macrolipophagy) results in the engulfment of LDs within double-membrane delimited structures ( ... ...

Abstract	Hepatocytes metabolize energy-rich cytoplasmic lipid droplets (LDs) in the lysosome-directed process of autophagy. An organelle-selective form of this process (macrolipophagy) results in the engulfment of LDs within double-membrane delimited structures (autophagosomes) before lysosomal fusion. Whether this is an exclusive autophagic mechanism used by hepatocytes to catabolize LDs is unclear. It is also unknown whether lysosomes alone might be sufficient to mediate LD turnover in the absence of an autophagosomal intermediate. We performed live-cell microscopy of hepatocytes to monitor the dynamic interactions between lysosomes and LDs in real-time. We additionally used a fluorescent variant of the LD-specific protein (PLIN2) that exhibits altered fluorescence in response to LD interactions with the lysosome. We find that mammalian lysosomes and LDs undergo interactions during which proteins and lipids can be transferred from LDs directly into lysosomes. Electron microscopy (EM) of primary hepatocytes or hepatocyte-derived cell lines supports the existence of these interactions. It reveals a dramatic process whereby the lipid contents of the LD can be "extruded" directly into the lysosomal lumen under nutrient-limited conditions. Significantly, these interactions are not affected by perturbations to crucial components of the canonical macroautophagy machinery and can occur in the absence of double-membrane lipoautophagosomes. These findings implicate the existence of an autophagic mechanism used by mammalian cells for the direct transfer of LD components into the lysosome for breakdown. This process further emphasizes the critical role of lysosomes in hepatic LD catabolism and provides insights into the mechanisms underlying lipid homeostasis in the liver.
MeSH term(s)	Animals ; Autophagosomes/metabolism ; Autophagy/physiology ; Cell Line ; Hepatocytes/metabolism ; Lipid Droplets/metabolism ; Lipid Metabolism ; Lysosomes/metabolism ; Mice ; Microscopy, Confocal ; Protein Transport ; Rats, Sprague-Dawley
Language	English
Publishing date	2020-12-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Video-Audio Media
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2011442117
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Article ; Online: FRET biosensors reveal AKAP-mediated shaping of subcellular PKA activity and a novel mode of Ca(2+)/PKA crosstalk.

Schott, Micah B / Gonowolo, Faith / Maliske, Benjamin / Grove, Bryon

Cellular signalling

2016 Volume 28, Issue 4, Page(s) 294–306

Abstract: Scaffold proteins play a critical role in cellular homeostasis by anchoring signaling enzymes in close proximity to downstream effectors. In addition to anchoring static enzyme complexes, some scaffold proteins also form dynamic signalosomes that can ... ...

Abstract	Scaffold proteins play a critical role in cellular homeostasis by anchoring signaling enzymes in close proximity to downstream effectors. In addition to anchoring static enzyme complexes, some scaffold proteins also form dynamic signalosomes that can traffic to different subcellular compartments upon stimulation. Gravin (AKAP12), a multivalent scaffold, anchors PKA and other enzymes to the plasma membrane under basal conditions, but upon [Ca(2+)]i elevation, is rapidly redistributed to the cytosol. Because gravin redistribution also impacts PKA localization, we postulate that gravin acts as a calcium "switch" that modulates PKA-substrate interactions at the plasma membrane, thus facilitating a novel crosstalk mechanism between Ca(2+) and PKA-dependent pathways. To assess this, we measured the impact of gravin-V5/His expression on compartmentalized PKA activity using the FRET biosensor AKAR3 in cultured cells. Upon treatment with forskolin or isoproterenol, cells expressing gravin-V5/His showed elevated levels of plasma membrane PKA activity, but cytosolic PKA activity levels were reduced compared with control cells lacking gravin. This effect required both gravin interaction with PKA and localization at the plasma membrane. Pretreatment with calcium-elevating agents thapsigargin or ATP caused gravin redistribution away from the plasma membrane and prevented gravin from elevating PKA activity levels at the membrane. Importantly, this mode of Ca(2+)/PKA crosstalk was not observed in cells expressing a gravin mutant that resisted calcium-mediated redistribution from the cell periphery. These results reveal that gravin impacts subcellular PKA activity levels through the spatial targeting of PKA, and that calcium elevation modulates downstream β-adrenergic/PKA signaling through gravin redistribution, thus supporting the hypothesis that gravin mediates crosstalk between Ca(2+) and PKA-dependent signaling pathways. Based on these results, AKAP localization dynamics may represent an important paradigm for the regulation of cellular signaling networks.
MeSH term(s)	A Kinase Anchor Proteins/genetics ; A Kinase Anchor Proteins/metabolism ; Calcium/metabolism ; Calcium Signaling/physiology ; Cell Line ; Cyclic AMP-Dependent Protein Kinases/genetics ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Fluorescence Resonance Energy Transfer ; Humans
Chemical Substances	A Kinase Anchor Proteins ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2016-04
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2016.01.001
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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