Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PKA has traditionally been thought as the binding protein of cAMP for mediating arginine vasopressin (AVP)-regulated osmotic water permeability in kidney collecting duct. It is now known that cAMP also exerts its effects via Epac (exchange protein directly activated by cAMP) and that intracellular Ca(2+) mobilization is necessary for AVP-induced apical exocytosis in inner medullary collecting duct (IMCD). The role of Epac as an effector of cAMP action in addition to PKA was investigated using confocal fluorescence microscopy in perfused IMCD. PKA inhibitors (1 microM H-89 or 10 microM KT-5720) at concentrations known to inhibit aquaporin-2 (AQP2) phosphorylation did not prevent AVP-induced Ca(2+) mobilization and oscillations. Epac-selective cAMP agonist (8-pCPT-2'-O-Me-cAMP) mimicked AVP in triggering Ca(2+) mobilization and oscillations, which was blocked by ryanodine but not by Rp-cAMP (a competitive antagonist of cAMP binding to PKA). 8-pCPT-2'-O-Me-cAMP also triggered apical exocytosis in the presence of a PKA inhibitor. Immunolocalization of AQP2 in perfused IMCD demonstrated that 8-pCPT-2'-O-Me-cAMP induces apical targeting of AQP2 and that AQP2 is abundant in junctional regions of basolateral membrane. Immunofluorescence study also confirmed the presence of Epac (isoform I) in IMCD. These results indicate that activation of Epac by an exogenous cAMP analog triggers intracellular Ca(2+) mobilization and apical exocytotic insertion of AQP2 in IMCD.
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PMID:Epac-mediated Ca(2+) mobilization and exocytosis in inner medullary collecting duct. 1668 23

Salivary secretion occurs in response to stimulation by neurotransmitters released from autonomic nerve endings. The molecular mechanisms underlying the secretion of water, a main component of saliva, from salivary glands are not known; the plasma membrane is a major barrier to water transport. A 28-kDa integral membrane protein, distributed in highly water-permeable tissues, was identified as a water channel protein, aquaporin (AQP). Thirteen AQPs (AQP0 - AQP12) have been identified in mammals. AQP5 is localized in lipid rafts under unstimulated conditions and translocates to the apical plasma membrane in rat parotid glands upon stimulation by muscarinic agonists. The importance of increases in intracellular calcium concentration [Ca(2+)](i) and the nitric oxide synthase and protein kinase G signaling pathway in the translocation of AQP5 is reviewed in section I. Signals generated by the activation of Ca(2+) mobilizing receptors simultaneously trigger and regulate exocytosis. Zymogen granule exocytosis occurs under the control of essential process, stimulus-secretion coupling, in salivary glands. Ca(2+) signaling is a principal signal in both protein and water secretion from salivary glands induced by cholinergic stimulation. On the other hand, the cyclic adenosine monophosphate (cAMP)/cAMP-dependent protein kinase system has a major role in zymogen granule exocytosis without significant increases in [Ca(2+)](i). In section II, the mechanisms underlying the control of salivary protein secretion and its dysfunction are reviewed.
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PMID:Water channels and zymogen granules in salivary glands. 1679 62

A new toad aquaporin (AQP) cDNA was cloned from a cDNA library constructed from the ventral skin of Xenopus laevis. This AQP (Xenopus AQP-x5) consisted of 273 amino acid residues with a high sequence homology to mammalian AQP5. The predicted amino acid sequence contained the two conserved Asn-Pro-Ala motifs found in all major intrinsic protein (MIP) family members and six putative transmembrane domains. The sequence also contained a mercurial-sensitive cysteine and a putative phosphorylation motif site for protein kinase A at Ser-257. The swelling assay using Xenopus oocytes revealed that AQP-x5 facilitated water permeability. Expression of AQP-x5 mRNA was restricted to the skin, brain, lungs and testes. Immunofluorescence and immunoelectron microscopical studies using an anti-peptide antibody (ST-156) against the C-terminal region of the AQP-x5 protein revealed the presence of immunopositive cells in the skin, with the label predominately localized in the apical plasma membrane of the secretory cells of the small granular glands. These glands are unique both in being close to the epidermal layer of the skin and in containing mitochondria-rich cells with vacuolar H+-ATPase dispersed among its secretory cells. Results from immunohistochemical experiments on the mucous or seromucous glands of several other anurans verified this result. We conclude that the presence of AQP-x5 in the apical plasma membrane of the small granular glands suggests its involvement in water secretion from the skins. The physiological roles of the AQP-x5 protein in the small or mucous glands are discussed.
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PMID:Molecular and cellular characterization of a new aquaporin, AQP-x5, specifically expressed in the small granular glands of Xenopus skin. 1688 67

All living beings need to solve the problem of controlled transport of water. To this purpose, a special group of integral membrane proteins called aquaporins has evolved. There are 13 known members of this family that act as channels for water and small solutes, such as glycerol and urea. Although they allow large flux of water, they successfully prevent passage of protons. Here, we present the review of the data from the literature on the selectivity mechanism of aquaporins. The regulation of aquaporin activity occurs through regulation of expression of their genes, changing the localization of the already existing proteins in the cells and direct regulation of the activity in situ. We present the review of new data on the mechanisms of direct regulation. Special emphasis is on the advances in comprehension of aquaporin-2 translocation in collecting tubule cells of the kidney. Four elements of this process are described: 1) the role of protein kinase A and phosphorylation of serine 256 on aquaporin-2, 2) the transport of vesicles along the microtubules toward the apical membrane, 3), the removal of cytoskeletal subapical obstruction and the role of Rho GTPase and ezrin-radixin-moesin proteins in this, and 4) elevation of the cytosolic Ca2+ concentration, the fusion of the vesicle with the apical membrane and the role of SNARE proteins in exocytosis.
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PMID:Regulation of selectivity and translocation of aquaporins: an update. 1711 90

In mammals, the hormonal regulation of water homeostasis is mediated by the aquaporin-2 water channel (Aqp2) of the collecting duct (CD). Vasopressin induces redistribution of Aqp2 from intracellular vesicles to the apical membrane of CD principal cells, accompanied by increased water permeability. Mutations of AQP2 gene in humans cause both recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. In this study, we generated a line of mice with the distal COOH-terminal tail of the Aqp2 deleted (Aqp2(Delta230)), including the protein kinase A phosphorylation site (S256), but still retaining the putative apical localization signal (221-229) at the COOH-terminal. Mice heterozygous for the truncation appear normal. Homozygotes are viable to adulthood, with reduced urine concentrating capacity, increased urine output, decreased urine osmolality, and increased daily water consumption. Desmopressin increased urine osmolality in wild-type mice but had no effect on Aqp2(Delta230/Delta230) mice. Kidneys from affected mice showed CD and pelvis dilatation and papillary atrophy. By immunohistochemical and immunoblot analyses using antibody against the NH(2)-terminal region of the protein Aqp2(Delta230/Delta230) mice had a markedly reduced protein abundance. Expression of the truncated protein in MDCK cells was consistent with a small amount of functional expression but no stimulation. Thus we have generated a mouse model of NDI that may be useful in studying the physiology and potential therapy of this disease.
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PMID:Nephrogenic diabetes insipidus in mice caused by deleting COOH-terminal tail of aquaporin-2. 1722 78

Previous RT-PCR experiments revealed the expression of gene transcripts for a variety of aquaporins in the neural retina, including aquaporin-0. We investigated by immunohistochemistry and Western blotting whether the aquaporin-0 protein is expressed in the retina of the rat. In addition to the lens, immunoreactivity for aquaporin-0 was expressed in the neural retina, but was absent in the pigment epithelium, choroidea, and sclera. In the neural retina, aquaporin-0 immunoreactivity was expressed by the nuclei and the synaptic terminals of protein kinase alpha- and beta-expressing bipolar and amacrine cells, and by the nuclei of neuronal cells in the ganglion cell layer. The immunoreactivity for aquaporin-0 did not co-localize with calbindin, a marker of horizontal cells, or with aquaporin-4, the glial water channel. Transient retinal ischemia caused a slight decrease in the retinal content of aquaporin-0, likely by degeneration of protein kinase alpha-expressing bipolar cells. It is concluded that aquaporin-0 may be involved in the regulation of the activity of retinal second order neurons.
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PMID:Localization of aquaporin-0 immunoreactivity in the rat retina. 1788 Nov 23

Vasopressin acts on the inner medullary collecting duct (IMCD) in the kidney to regulate water and urea transport. To obtain a "parts list" of gene products expressed in the IMCD, we carried out mRNA profiling of freshly isolated rat IMCD cells using Affymetrix Rat 230 2.0 microarrays with approximately 31,000 features; 7,913 annotated transcripts were found to be expressed above background in the IMCD cells. We have created a new online database (the "IMCD Transcriptome Database;" http://dir.nhlbi.nih.gov/papers/lkem/imcdtr/) to make the results publicly accessible. Among the 30 transcripts with the greatest signals on the arrays were 3 water channels: aquaporin-2, aquaporin-3, and aquaporin-4, all of which have been reported to be targets for regulation by vasopressin. In addition, the transcript with the greatest signal among members of the solute carrier family of genes was the UT-A urea transporter (Slc14a2), which is also regulated by vasopressin. The V2 vasopressin receptor was strongly expressed, but the V1a and V1b vasopressin receptors did not produce signals above background. Among the 200 protein kinases expressed, the serum-glucocorticoid-regulated kinase (Sgk1) had the greatest signal intensity in the IMCD. WNK1 and WNK4 were also expressed in the IMCD with a relatively high signal intensity, as was protein kinase A (beta-catalytic subunit). In addition, a large number of transcripts corresponding to A kinase anchoring proteins and 14-3-3 proteins (phospho-S/T-binding proteins) were expressed. Altogether, the results combine with proteomics studies of the IMCD to provide a framework for modeling complex interaction networks responsible for vasopressin action in collecting duct cells.
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PMID:Transcriptional profiling of native inner medullary collecting duct cells from rat kidney. 1795 98

It has been the general consensus that cAMP-mediated PKA-dependent phosphorylation of aquaporin-2 is the primary mechanism of vasopressin to regulate osmotic water permeability in kidney collecting duct. By using laser scanning confocal microscopy to monitor [Ca2+]i and apical exocytosis in individual cells of inner medullary collecting duct, we have demonstrated that vasopressin also triggers intracellular Ca2+ mobilization, which is coupled to apical exocytotic insertion of aquaporin-2. Vasopressin-induced Ca2+ mobilization is in the form of oscillations, which involves both intracellular Ca2+ release from ryanodine-gated Ca2+ stores and extracellular Ca2+ influx via capacitative calcium entry. Each individual cell operates as an independent calcium oscillator with time variance in frequency and amplitude. Vasopressin-induced Ca2+ mobilization is mediated by cAMP, but is independent of PKA. Exogenous cAMP analog (8-pCPT-2'-O-Me-cAMP), which activates Epac (exchange protein directly activated by cAMP), but not PKA, triggers Ca2+ mobilization and apical exocytosis. These observations suggest that activation of Epac by cAMP may also contribute to the action of vasopressin in regulating osmotic water permeability. There are multiple plausible candidates for downstream effectors of vasopressin-induced Ca2+ signal including calmodulin, myosin light chain kinase, calmodulin kinase II, and calcineurin. All of them have been implicated in the regulation of aquaporin-2 trafficking and/or water permeability.
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PMID:Calcium signaling in vasopressin-induced aquaporin-2 trafficking. 1795 81

Cyclic adenosine monophosphate (cAMP) is a central second messenger controlling a plethora of vital functions. Studies of cAMP dynamics in living cells have revealed markedly inhomogeneous concentrations of the second messenger in different compartments. Moreover, cAMP effectors such as cAMP-dependent protein kinase (PKA) and cAMP-activated GTP-exchange factors (Epacs) are tethered to specific cellular sites. Both the tailoring of cAMP concentrations, and the activities of cAMP-dependent signalling systems at specific cellular locations are prerequisites for most, if not all, cAMP-dependent processes. This review focuses on the role of compartmentalized cAMP signalling in exocytic processes in non-neuronal cells. Particularly, the insertion of aquaporin-2 into the plasma membrane of renal principal cells as an example for a cAMP-dependent exocytic process in a non-secretory cell type, renin secretion from juxtaglomerular cells as a cAMP-triggered exocytosis from an endocrine cell, insulin release from pancreatic beta-cells as a Ca2+-mediated and cAMP-potentiated exocytic processes in an endocrine cell, and cAMP- or Ca2+ -triggered H+ secretion from gastric parietal cells as an exocytic process in an exocrine cell are discussed. The selected examples of cAMP-regulated exocytic pathways are reviewed with regard to key proteins involved: adenylyl cyclases, phosphodiesterases, PKA, A kinase anchoring proteins (AKAPs) and Epacs.
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PMID:Compartmentalized cAMP signalling in regulated exocytic processes in non-neuronal cells. 1806 3

In the kidney, many physiological processes of ion transport and cellular proliferation are mediated via cAMP, which classically activates protein kinase A (PKA). Recently, however, two new cAMP targets, the exchange protein directly activated by cAMP (Epac) 1 and 2, were identified, which mediate alternative pathways to PKA. To investigate their renal expression, antibodies specifically recognizing Epac1 and Epac2 were generated and used in rat immunohistochemistry with antibodies recognizing aquaporin-1 (AQP1), Tamm-Horsfall protein, Calbindin-D(28K), and AQP2 to mark proximal tubules (PT)/thin descending limbs of Henle's loop (tDLH), thick ascending limbs of Henle's loop (TAL), distal convoluted tubule/connecting tubule (DCT/CNT), and the collecting duct (CD) principal cells, respectively. Epac1 and Epac2 were expressed at the brush border of PT cells but were absent from tDLH cells. In the TAL, Epac1 and Epac2 were expressed throughout the cells with some confinement toward the apical membrane. In the DCT/CNT, Epac1 was confined to the apical region of the cells, whereas Epac2 was mainly expressed in the apical and basolateral regions. In the CD, a dispersed Epac1 expression was found in intercalated cells only (cortical CD), principal and intercalated cells [outer medullary CD (OMCD)], and mainly AQP2-negative cells in the inner medullary CD (IMCD). In contrast, Epac2 expression was at the apical and basolateral membrane of cortical principal cells, dispersed and apical in the OMCD, and in all cells of the IMCD. A similar distribution for Epac1/2 was found in the human kidney. The observed expression in different tubular segments suggests a major role for Epac 1/2 in tubular transport physiology and cellular proliferation.
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PMID:Renal expression of exchange protein directly activated by cAMP (Epac) 1 and 2. 1849 99


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