A-kinase anchoring protein 79/150 facilitates the phosphorylation of GABAA receptors by cAMP-dependent protein kinase via selective interaction with receptor β subunits

Brandon, Nicholas J.; Jovanovic, Jasmina N.; Colledge, Marcie; Kittler, Josef T.; Brandon, Julia M.; Scott, John D.; Moss, Stephen J.

doi:10.1016/s1044-7431(02)00017-9

Cited by 96 publications

(67 citation statements)

References 43 publications

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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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“…715035150 and 715035152). The following constructs were used: GST fusion protein constructs encoding the large intracellular loop of GABA A R subunits ␣1, ␣2, ␤3, and ␥2 as described previously (11,12). FLAG-ephexin was provided by M. E. Greenberg (Harvard University), as described previously (13).…”

Section: Methodsmentioning

confidence: 99%

Proteomic Characterization of Inhibitory Synapses Using a Novel pHluorin-tagged γ-Aminobutyric Acid Receptor, Type A (GABAA), α2 Subunit Knock-in Mouse

Nakamura

Morrow

Modgil

et al. 2016

Journal of Biological Chemistry

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The accumulation of ␥-aminobutyric acid receptors (GABA A Rs) at the appropriate postsynaptic sites is critical for determining the efficacy of fast inhibitory neurotransmission. Although we know that the majority of synaptic GABA A R subtypes are assembled from ␣1-3, ␤, and ␥2 subunits, our understanding of how neurons facilitate their targeting to and stabilization at inhibitory synapses is rudimentary. To address these issues, we have created knock-in mice in which the pH-sensitive green fluorescent protein (GFP) and the Myc epitope were introduced to the extracellular domain of the mature receptor ␣2 subunit (pH␣2). Using immunoaffinity purification and mass spectroscopy, we identified a stable complex of 174 proteins that were associated with pH␣2, including other GABA A R subunits, and previously identified receptor-associated proteins such as gephyrin and collybistin. 149 of these proteins were novel GABA A R binding partners and included G-protein-coupled receptors and ion channel subunits, proteins that regulate trafficking and degradation, regulators of protein phosphorylation, GTPases, and a number of proteins that regulate their activity. Notably, members of the postsynaptic density family of proteins that are critical components of excitatory synapses were not associated with GABA A Rs. Crucially, we demonstrated for a subset of these novel proteins (including cullin1, ephexin, potassium channel tetramerization domain containing protein 12, mitofusin2, metabotropic glutamate receptor 5, p21-activated kinase 7, and Ras-related protein 5A) bind directly to the intracellular domains of GABA A Rs, validating our proteomic analysis. Thus, our experiments illustrate the complexity of the GABA A R proteome and enhance our understanding of the mechanisms neurons use to construct inhibitory synapses.

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“…In addition to compelling data for inclusion of PKA, PKC, CaN, β 2 AR, Src and GRK2 [69] in the AKAP79/250 signalling complexes, others have reported the association of AMPA/kainate-sensitive glutamate receptors [49,70], NMDA receptors [71], the Kir2.1 ion channel [72], L-type calcium channels [73], GABA A (γ -aminobutyric acid A) receptors [74], as well as cytoskeletal elements [35,71] in these complexes. It is likely that GPCRs other than the β 2 AR make use of AKAPbased signalling complexes, although the reagents available for dependable screening of the multitude of GPCRs are far more limited.…”

Section: Probing For Novel Akap-associated Proteinsmentioning

confidence: 99%

AKAPs (A-kinase anchoring proteins) and molecules that compose their G-protein-coupled receptor signalling complexes

Malbon

Tao

Wang

2004

Biochemical Journal

100

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Cell signalling mediated via GPCRs (G-protein-coupled receptors) is a major paradigm in biology, involving the assembly of receptors, G-proteins, effectors and downstream elements into complexes that approach in design 'solid-state' signalling devices. Scaffold molecules, such as the AKAPs (A-kinase anchoring proteins), were discovered more than a decade ago and represent dynamic platforms, enabling multivalent signalling. AKAP79 and AKAP250 were the first to be shown to bind to membrane-embedded GPCRs, orchestrating the interactions of various protein kinases (including tyrosine kinases), protein phosphatases (e.g. calcineurin) and cytoskeletal elements with at least one member of the superfamily of GPCRs, the prototypical β 2 -adrenergic receptor. In this review, the multivalent interactions of AKAP250 with the cell membrane, receptor, cytoskeleton and constituent components are detailed, providing a working model for AKAP-based GPCR signalling complexes. Dynamic regulation of the AKAP-receptor complex is mediated by ordered protein phosphorylation.

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A-kinase anchoring protein 79/150 facilitates the phosphorylation of GABAA receptors by cAMP-dependent protein kinase via selective interaction with receptor β subunits

Cited by 96 publications

References 43 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

Proteomic Characterization of Inhibitory Synapses Using a Novel pHluorin-tagged γ-Aminobutyric Acid Receptor, Type A (GABAA), α2 Subunit Knock-in Mouse

AKAPs (A-kinase anchoring proteins) and molecules that compose their G-protein-coupled receptor signalling complexes

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