Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The distal tubule reabsorbs approximately 10% of the filtered Mg(2+), but this is 70-80% of that delivered from the loop of Henle. Because there is little Mg(2+) reabsorption beyond the distal tubule, this segment plays an important role in determining the final urinary excretion. The distal convoluted segment (DCT) is characterized by a negative luminal voltage and high intercellular resistance so that Mg(2+) reabsorption is transcellular and active. This review discusses recent evidence for selective and sensitive control of Mg(2+) transport in the DCT and emphasizes the importance of this control in normal and abnormal renal Mg(2+) conservation. Normally, Mg(2+) absorption is load dependent in the distal tubule, whether delivery is altered by increasing luminal Mg(2+) concentration or increasing the flow rate into the DCT. With the use of microfluorescent studies with an established mouse distal convoluted tubule (MDCT) cell line, it was shown that Mg(2+) uptake was concentration and voltage dependent. Peptide hormones such as parathyroid hormone, calcitonin, glucagon, and arginine vasopressin enhance Mg(2+) absorption in the distal tubule and stimulate Mg(2+) uptake into MDCT cells. Prostaglandin E(2) and isoproterenol increase Mg(2+) entry into MDCT cells. The current evidence indicates that cAMP-dependent protein kinase A, phospholipase C, and protein kinase C signaling pathways are involved in these responses. Steroid hormones have significant effects on distal Mg(2+) transport. Aldosterone does not alter basal Mg(2+) uptake but potentiates hormone-stimulated Mg(2+) entry in MDCT cells by increasing hormone-mediated cAMP formation. 1,25-Dihydroxyvitamin D(3), on the other hand, stimulates basal Mg(2+) uptake. Elevation of plasma Mg(2+) or Ca(2+) inhibits hormone-stimulated cAMP accumulation and Mg(2+) uptake in MDCT cells through activation of extracellular Ca(2+)/Mg(2+)-sensing mechanisms. Mg(2+) restriction selectively increases Mg(2+) uptake with no effect on Ca(2+) absorption. This intrinsic cellular adaptation provides the sensitive and selective control of distal Mg(2+) transport. The distally acting diuretics amiloride and chlorothiazide stimulate Mg(2+) uptake in MDCT cells acting through changes in membrane voltage. A number of familial and acquired disorders have been described that emphasize the diversity of cellular controls affecting renal Mg(2+) balance. Although it is clear that many influences affect Mg(2+) transport within the DCT, the transport processes have not been identified.
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PMID:Magnesium transport in the renal distal convoluted tubule. 1115 54

Medullary neurons containing pituitary adenylate cyclase-activating polypeptide (PACAP) and noradrenalin (NA) project to the hypothalamus and they are involved in the regulation of arginine vasopressin (AVP) neurons. At the ultrastructural level, PACAP immunoreactivity was detected in the granular vesicles in catecholaminergic nerve terminals that made synaptic contact with AVP neurons. Both PACAP (at least 1 nM) and NA (at least 1 microM) induced large increases in the cytosolic Ca2+ concentration ([Ca2+]i) in isolated AVP cells. PACAP at 0.1 nM and NA at 0.1 microM had little effects, if any, on [Ca2+]i. However, when 0.1 nM PACAP and 0.1 microM NA were combined, they evoked large increase in [Ca2+]i in AVP neurons. An inhibitor of protein kinase A (PKA) completely inhibited the PACAP-induced increase in [Ca2+]i, but only partly inhibited the NA-induced increase in [Ca2+]i. In AVP cells that were prelabeled with quinacrine, PACAP and NA acted synergistically to induce a loss of quinacrine fluorescence, indicating secretion of neurosecretory granules in AVP neurons. The results suggest that PACAP and NA, coreleased from the same nerve terminals, act in synergy to evoke calcium signaling and secretion in AVP neurons, and that the synergism is mediated by the interaction between cAMP-PKA pathway an as yet unidentified factor "X" linked to L-type Ca2+ channels. The synergism between PACAP and NA may contribute to the regulation of AVP secretion under physiological conditions.
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PMID:Functional significance of colocalization of PACAP and catecholamine in nerve terminals. 1119 25

Recent progress in research on pituitary adenylate-activating polypeptide (PACAP) with a special emphasis on the brain is reviewed. PACAP is a pleiotropic neuropeptide that belongs to the secretin/glucagon/vasoactive intestinal peptide family. PACAP functions as a hypothalamic hormone, neurotransmitter, neuromodulator, and neurotrophic factor. Studies on the gene encoding the PACAP precursor and the specific PACAP receptor (PAC1-R) and its subtypes have provided information on the control of gene expression for PACAP, and the relationship between the receptor subtypes and the signal transduction pathways. The PAC1-R is a G protein-coupled receptor with seven transmembrane domains and belongs to the VIP receptor family. At least eight subtypes of PAC1-R result from alternate splicing. Each subtype is coupled to specific signaling pathways, and its expression is tissue or cell specific. PACAP stimulates the release of arginine vasopressin and increases cytosolic Ca2+ ([Ca2+]i). PACAP serves as a neurotransmitter and/or neuromodulator and the activation of the PAC1-R stimulates a cAMP-protein kinase A signal transduction pathway which in turn evokes the [Ca2+]i signaling system. More importantly, PACAP is a neurotrophic factor that may play an important role during the development of the brain. The PAC1-R is actively expressed in different neuroepithelia from early developmental stages and expressed in various brain regions during prenatal and postnatal development. In the adult brain, PACAP appears to function as a neuroprotective factor that attenuates the neuronal damage resulting from various insults.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptors in the brain. 1119 92

The antidiuretic hormone arginine vasopressin (AVP) regulates water reabsorption in renal principal cells by inducing a cAMP/protein kinase A-dependent translocation of water channels [aquaporin-2 (AQP2)] from intracellular vesicles into the apical cell membranes. Using primary cultured rat inner medullary collecting duct (IMCD) cells, it has been shown that AQP2 translocation in response to AVP stimulation occurs only if protein kinase A (PKA) is anchored to PKA anchoring proteins (AKAPs), which are present in various subcellular compartments. The identity of the AKAPs involved has not yet been elucidated. One potential candidate is a new splice variant of AKAP18, namely AKAP18 delta.
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PMID:Role and identification of protein kinase A anchoring proteins in vasopressin-mediated aquaporin-2 translocation. 1147 24

Lewis (LEW/N) rats, compared to Fischer (F344/N) rats, are susceptible to inflammatory/autoimmune diseases, in part, as a result of their blunted hypothalamic-pituitary-adrenal (HPA) axis responses. We examined regulation of LEW/N and F344/N fetal hypothalamic cell secretion of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), two major HPA axis mediators, by inflammatory and neurotransmitter stimuli. Interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and protein kinase A (PKA) and protein kinase C (PKC) activators did not affect LEW/N basal secretion. Compared to F344/N, LEW/N cells were hyporesponsive to lipopolysaccharide (LPS), serotonin (5-HT), and acetylcholine chloride (ACh). However, LPS-induced AVP release and ACh-evoked CRH secretion in LEW/N were comparable with those of F344/N. Our findings suggest that the blunted LEW/N neuropeptide response was more likely related to components of second messenger systems, rather than to any one specific stimulus.
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PMID:Specific up-regulation of CRH or AVP secretion by acetylcholine or lipopolysaccharide in inflammatory susceptible Lewis rat fetal hypothalamic cells. 1245 34

The peptide angiotensin-(1-7) [Ang-(1-7)] is known to enhance water transport in rat inner medullary collecting duct (IMCD). The aim of this study was to determine the mechanism of the Ang-(1-7) effect on osmotic water permeability (Pf). Pf was measured in the normal rat IMCD perfused in vitro in presence of agonists [Ang-(1-7), arginine vasopressin (AVP) and Ang-(3-8)], and antagonists of the angiotensin and the vasopressin cascade. Ang-(1-7), but not Ang-(3-8), increased Pf significantly. The effect of Ang-(1-7) on Pf was abolished by its selective antagonist, A-779, added before or after Ang-(1-7). Prostaglandin E2 and the protein kinase A inhibitor H8 also blocked the Ang-(1-7) effect. Blockade of vasopressin V1 receptors by antagonists did not change the Ang-(1-7) effect, but pre-treatment with a V2 antagonist abolished the effect of Ang-(1-7) on Pf. Similarly, pre-treatment with A-779 inhibited AVP's effect on Pf. Forskolin-stimulated Pf was blocked both by A-779 and by the V2 antagonist. Finally, Ang-(1-7) increased cAMP levels in fresh IMCD cell suspensions whilst the forskolin-stimulated cAMP synthesis was decreased by A-779 and the V2 antagonist. These data provide evidence that Ang-(1-7) interacts via its receptor with the AVP V2 system through a mechanism involving adenylate-cyclase activation.
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PMID:Angiotensin-(1-7) stimulates water transport in rat inner medullary collecting duct: evidence for involvement of vasopressin V2 receptors. 1453 90

Aquaporin-4 (AQP4) water channels exist as heterotetramers of M1 and M23 splice variants and appear to be present in orthogonal arrays of intramembraneous particles (OAPs) visualized by freeze-fracture microscopy. We report that AQP4 forms OAPs in rat gastric parietal cells but not in parietal cells from the mouse or kangaroo rat. Furthermore, the organization of principal cell OAPs in Brattleboro rat kidney is perturbed by vasopressin (arginine vasopressin). Membranes of LLC-PK(1) cells expressing M23-AQP4 showed large, abundant OAPs, but none were detectable in cells expressing M1-AQP4. Measurements of osmotic swelling of transfected LLC-PK(1) cells using videomicroscopy, gave osmotic water permeability coefficient (P(f)) values (in cm/s) of 0.018 (M1-AQP4), 0.019 (M23-AQP4), and 0.003 (control). Quantitative immunoblot and immunofluorescence showed an eightfold greater expression of M1- over M23-AQP4 in the cell lines, suggesting that single-channel p(f) (cm(3)/s) is much greater for the M23 variant. Somatic fusion of M1- and M23-AQP4 cells (P(f) = 0.028 cm/s) yielded OAPs that were fewer and smaller than in M23 cells alone, and M1-to-M23 expression ratios ( approximately 1:4) normalized to AQP4 in M1 or M23 cells indicated a reduced single-channel p(f) for the M23 variant. Expression of an M23-AQP4-Ser(111E) mutant produced approximately 1.5-fold greater single-channel p(f) and OAPs that were up to 2.5-fold larger than wild-type M23-AQP4 OAPs, suggesting that a putative PKA phosphorylation site Ser(111) is involved in OAP formation. We conclude that the higher-order organization of AQP4 in OAPs increases single-channel osmotic water permeability by one order of magnitude and that differential cellular expression levels of the two isoforms could regulate this organization.
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PMID:Membrane organization and function of M1 and M23 isoforms of aquaporin-4 in epithelial cells. 1514 73

The antidiuretic hormone arginine vasopressin increases the osmotic water permeability of the renal collecting ducts by inducing the shuttling of aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical plasma membrane of the principal cells. This process has been demonstrated to be dependent on the cytoskeleton and protein kinase A (PKA). Previous studies in the toad urinary bladder, a functional homologue of the renal collecting duct, have demonstrated that the sulfhydryl reagent N-ethylmaleimide (NEM) is also able to activate the vasopressin-sensitive water permeability pathway in this tissue. The aim of the present study was to investigate the effects of NEM on AQP2 trafficking in a mammalian system. We show that NEM causes translocation of AQP2 from the cytosol to the plasma membrane in rat inner medullary collecting ducts; like the response to arginine vasopressin, this action was also dependent on an intact cytoskeleton and PKA. This effect is not mediated by cAMP but results from direct activation of PKA by NEM.
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PMID:N-ethylmaleimide causes aquaporin-2 trafficking in the renal inner medullary collecting duct by direct activation of protein kinase A. 1553 72

Prevailing expression levels of aquaporin-2 (AQP2) mRNA play a major role in regulating AQP2 protein abundance. Here, we investigated whether AQP2 protein abundance is regulated at a posttranscriptional level as well. The expression levels of both AQP2 mRNA and protein increase in response to arginine vasopressin (AVP) in a concentration- and time-dependent manner in cultured immortalized mouse collecting duct principal cells (mpkCCD(cl4) cells). AVP washout from the medium of AVP-pretreated cells revealed that AQP2 mRNA expression progressively decreased over time, whereas AQP2 protein abundance first increased immediately after AVP washout and then gradually decreased over time. Inversely, increasing AVP concentration led to a time-dependent increase of AQP2 mRNA, whereas AQP2 protein abundance first decreased immediately after AVP supplementation and then gradually increased over time. These transient effects arose from altered V2-receptor activity because they could be abolished by SR-121463B, a specific V2-receptor antagonist. Although cycloheximide administration had no effect on transient alterations of AQP2 protein content, these effects were attenuated by administration of chloroquine, a lysosomal inhibitor, or lactacystin, a proteasomal inhibitor. Short-term inhibition of PKA activity significantly increased AQP2 protein abundance and blunted the transient alterations of AQP2 protein content induced by AVP washout and supplementation. In addition, phosphorylated AQP2 abundance increased immediately after AVP supplementation. These results indicate that in response to AVP AQP2 protein abundance in collecting duct principal cells is principally influenced by AQP2 mRNA content but is additionally regulated by PKA-dependent negative feedback acting on AQP2 protein degradation.
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PMID:Posttranscriptional control of aquaporin-2 abundance by vasopressin in renal collecting duct principal cells. 1598 52

Water homeostasis in humans is regulated by vasopressin, which induces the translocation of homotetrameric aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical membrane of renal principal cells. For this process, phosphorylation of AQP2 at S256 by cAMP-dependent protein kinase A is thought to be essential. Mutations in the AQP2 gene cause recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. Here, a family in which dominant NDI was caused by an exchange of arginine 254 by leucine in the intracellular C terminus of AQP2 (AQP2-R254L), which destroys the protein kinase A consensus site, was identified. Expressed in oocytes, AQP2-R254L appeared to be a functional water channel but was impaired in its transport to the cell surface to the same degree as AQP2-S256A, which mimics nonphosphorylated AQP2. In polarized renal cells, AQP2-R254L was retained intracellularly and was distributed similarly as AQP2-S256A or wild-type AQP2 in unstimulated cells. Upon co-expression in MDCK cells, AQP2-R254L interacted with and retained wild-type AQP2 in intracellular vesicles. Furthermore, AQP2-R254L had a low basal phosphorylation level, which was not increased with forskolin, and mimicking constitutive phosphorylation in AQP2-R254L with the S256D mutation shifted its expression to the basolateral and apical membrane. These data indicate that dominant NDI in this family is due to a R254L mutation, resulting in the loss of arginine vasopressin-mediated phosphorylation of AQP2 at S256, and illustrates the in vivo importance of phosphorylation of AQP2 at S256 for the first time.
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PMID:Lack of arginine vasopressin-induced phosphorylation of aquaporin-2 mutant AQP2-R254L explains dominant nephrogenic diabetes insipidus. 1614 36


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