Role for A Kinase-anchoring Proteins (AKAPS) in Glutamate Receptor Trafficking and Long Term Synaptic Depression

Snyder, Eric M.; Colledge, Marcie; Crozier, Robert A.; Chen, Wendy S.; Scott, John D.; Bear, Mark F.

doi:10.1074/jbc.m409693200

Cited by 108 publications

(122 citation statements)

References 44 publications

(51 reference statements)

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“…Consequently, PKA phosphorylation events that augment AQP2 pore function must proceed through other AKAP-associated pools of this kinase. Likely candidates include AKAP18δ, a PKAanchoring protein that codistributes, but does not interact with, AQP2, and AKAP79/150 that tethers PKA to membrane-proximal regions (48)(49)(50)(51). There is clear precedent for AKAPs that participate in PKA-independent signaling events.…”

Section: Discussionmentioning

confidence: 99%

AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption

Whiting

Ogier

Forbush

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Filtration through the kidney eliminates toxins, manages electrolyte balance, and controls water homeostasis. Reabsorption of water from the luminal fluid of the nephron occurs through aquaporin-2 (AQP2) water pores in principal cells that line the kidney-collecting duct. This vital process is impeded by formation of an "actin barrier" that obstructs the passive transit of AQP2 to the plasma membrane. Bidirectional control of AQP2 trafficking is managed by hormones and signaling enzymes. We have discovered that vasopressin-independent facets of this homeostatic mechanism are under the control of A-Kinase Anchoring Protein 220 (AKAP220; product of the Akap11 gene). CRISPR/Cas9 gene editing and imaging approaches show that loss of AKAP220 disrupts apical actin networks in organoid cultures. Similar defects are evident in tissue sections from AKAP220-KO mice. Biochemical analysis of AKAP220-null kidney extracts detected reduced levels of active RhoA GTPase, a well-known modulator of the actin cytoskeleton. Fluorescent imaging of kidney sections from these genetically modified mice revealed that RhoA and AQP2 accumulate at the apical surface of the collecting duct. Consequently, these animals are unable to appropriately dilute urine in response to overhydration. We propose that membrane-proximal signaling complexes constrained by AKAP220 impact the actin barrier dynamics and AQP2 trafficking to ensure water homeostasis. yet only approximately 1.5 L of urine is excreted. The majority of this water is reabsorbed from the luminal fluid of the nephron (1). Regulated water reabsorption in response to dehydration occurs through aquaporin-2 (AQP2) water pores in the principal cells of the collecting duct (2). This is stimulated by the hormone arginine vasopressin (AVP). Vasopressin induces PKA phosphorylation of serine 256 on AQP2 and stimulates its translocation from intracellular vesicles to the apical membranes of cells lining the collecting ducts. Reabsorption of water through the kidney preserves fluid balance and results in more concentrated urine (3, 4). Conversely, when an animal ingests excess water, decreased plasma osmolality inhibits vasopressin release, and AQP2 is recovered from the apical membrane by endocytosis. This renders the collecting duct impermeable to water, thereby diverting excess water through the ureter to the bladder.Not surprisingly, defects in AQP2 trafficking have pathophysiological outcomes. For example, nephrogenic diabetes insipidus (NDI) is associated with impaired vasopressin signaling to AQP2 (5-8). Symptoms include excessive thirst, excretion of a large volume of dilute urine, and electrolyte imbalances, including hypernatremia (1, 5). Hereditary forms of this disease appear in patients with inactivating mutations in the V2 vasopressin receptor (V2R) or AQP2 (9-12). Thus, understanding the molecular mechanisms that govern bidirectional control of AQP2 location may lead to new therapeutic approaches for the treatment of NDI.Although the enzymes and effector proteins that govern AQP2 in...

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Section: Discussionmentioning

confidence: 99%

AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption

Whiting

Ogier

Forbush

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This prevents PKA from interacting with AKAPs. Ht31 has been frequently used to complement PKI by removing PKA from AKAP, thereby abolishing localized PKA activity (13). When we treated cells with 5 M st-Ht31, a stearated and thus membrane-permeable form, we were surprised to see that both BHK cells and RAW macrophages robustly released microparticles, indicated by the presence of cholesterol in the medium, or cholesterol efflux, in the absence of extracellular acceptors (Fig.…”

Section: St-ht31 Induces Robust Microparticle Release In the Absencementioning

confidence: 94%

Ht31, a Protein Kinase A Anchoring Inhibitor, Induces Robust Cholesterol Efflux and Reverses Macrophage Foam Cell Formation through ATP-binding Cassette Transporter A1

Fang

Denis

et al. 2011

Journal of Biological Chemistry

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Macrophage foam cell is the predominant cell type in atherosclerotic lesions. Removal of excess cholesterol from macrophages thus offers effective protection against atherosclerosis. Here we report that a protein kinase A (PKA)-anchoring inhibitor, st-Ht31, induces robust cholesterol/phospholipid efflux, and ATP-binding cassette transporter A1 (ABCA1) greatly facilitates this process. Remarkably, we found that st-Ht31 completely reverses foam cell formation, and this process is ABCA1-dependent. The reversal is also accompanied by the restoration of well modulated inflammatory response to LPS. There is no detectable toxicity associated with st-Ht31, even when cells export up to 20% cellular cholesterol per hour. Using FRET-based PKA biosensors in live cells, we provide evidence that st-Ht31 drives cholesterol efflux by elevating PKA activity specifically in the cytoplasm. Furthermore, ABCA1 facilitates st-Ht31 uptake. This allows st-Ht31 to effectively remove cholesterol from ABCA1-expressing cells. We speculate that de-anchoring of PKA offers a novel therapeutic strategy to remove excess cholesterol from lipid-laden lesion macrophages.

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“…In addition to a role in signal transduction, several AKAPs facilitate the trafficking of their anchored cargo, including that of membrane bound proteins such as aquaporin-2, the NMDA receptor, and ␤-adrenergic receptors (25)(26)(27)(28)(29). AC2 is targeted to the plasma membrane as part of a preassembled signaling complex that includes the ␤2-adrenergic receptor (30).…”

Section: Role Of Ac Isoforms In Yotiao Complexesmentioning

confidence: 99%

The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain

Piggott

Bauman

Scott

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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A-kinase anchoring proteins (AKAPs) influence the spatial and temporal regulation of cAMP signaling events. Anchoring of PKA in proximity to certain adenylyl cyclase (AC) isoforms is thought to enhance the phosphorylation dependent termination of cAMP synthesis. Using a combination of immunoprecipitation and enzymological approaches, we show that the plasma membrane targeted anchoring protein AKAP9/Yotiao displays unique specificity for interaction and the regulation of a variety of AC isoforms. Yotiao inhibits AC 2 and 3, but has no effect on AC 1 or 9, serving purely as a scaffold for these latter isoforms. Thus, Yotiao represents an inhibitor of AC2. The N terminus of AC2 (AC2-NT), which binds directly to amino acids 808 -957 of Yotiao, mediates this interaction. Additionally, AC2-NT and Yotiao (808 -957) are able to effectively inhibit the association of AC2 with Yotiao and, thus, reverse the inhibition of AC2 by Yotiao in membranes. Finally, disruption of Yotiao-AC interactions gives rise to a 40% increase in brain AC activity, indicating that this anchoring protein functions to directly regulate cAMP production in the brain. 2). This family of proteins functions to target PKA and other cAMP effector proteins to specific regions of the cell allowing for increased signaling specificity. Several members of this diverse protein family bind other receptors, channels, or enzymes to form tightly regulated signaling modules, facilitating PKA interactions with its downstream effectors. In addition, these signaling modules often constitute feedback loops between kinases and phosphatases or recruit phosphodiesterases to terminate the cAMP signal (3).Our labs previously identified a complex containing AKAP79/ 150 and type 5 adenylyl cyclase (AC), that facilitates the spatiotemporal organization of cAMP signaling (4). AKAP79 inhibits AC5 activity, while providing a mechanism for feedback inhibition via PKA phosphorylation of anchored AC5. However, with Ϸ30 gene families of AKAPs identified thus far, and nine mammalian isoforms of AC, it begs the question, does AKAP scaffolding of AC and PKA represent a general paradigm for cAMP signaling? The AKAP Yotiao represents an ideal test case to begin to address this question. Yotiao is a splice variant of the AKAP9 gene and is present on the plasma membrane (5, 6). In addition to PKA, Yotiao binds protein phosphatase 1 (PP1), NMDA receptors, the heart potassium channel subunit KCNQ1, and the IP 3 R1 (5, 7-9). Interestingly, AKAP anchored PKA phosphorylation of the NMDA receptor, KCNQ1, and IP 3 R1 is necessary for each effector's normal function (8-11). For example, disruption of the KCNQ1 association with Yotiao gives rise to long QT syndrome, a type of heart arrhythmia that can be fatal (12). The requirement for a tight coupling between PKA and KCNQ1, and other effectors suggests that cAMP production must also be tightly regulated, perhaps as even part of this complex.We now show that Yotiao is associated with brain and heart adenylyl cyclases. Yotiao displays specificity am...

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Role for A Kinase-anchoring Proteins (AKAPS) in Glutamate Receptor Trafficking and Long Term Synaptic Depression

Cited by 108 publications

References 44 publications

AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption

AKAP220 manages apical actin networks that coordinate aquaporin-2 location and renal water reabsorption

Ht31, a Protein Kinase A Anchoring Inhibitor, Induces Robust Cholesterol Efflux and Reverses Macrophage Foam Cell Formation through ATP-binding Cassette Transporter A1

The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain

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