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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cardiac ATP-sensitive K(+) (K(ATP)) channels, gated by cellular metabolism, are formed by association of the inwardly rectifying potassium channel Kir6.2, the potassium conducting subunit, and SUR2A, the ATP-binding cassette protein that serves as the regulatory subunit. Kir6.2 is the principal site of ATP-induced channel inhibition, while SUR2A regulates K(+) flux through adenine nucleotide binding and catalysis. The ATPase-driven conformations within the regulatory SUR2A subunit of the K(ATP) channel complex have determinate linkage with the states of the channel's pore. The probability and life-time of ATPase-induced SUR2A intermediates, rather than competitive nucleotide binding alone, defines nucleotide-dependent K(ATP) channel gating. Cooperative interaction, instead of independent contribution of individual nucleotide binding domains within the SUR2A subunit, serves a decisive role in defining K(ATP) channel behavior. Integration of K(ATP) channels with the cellular energetic network renders these channel/enzyme heteromultimers high-fidelity metabolic sensors. This vital function is facilitated through phosphotransfer enzyme-mediated transmission of controllable energetic signals. By virtue of coupling with cellular energetic networks and the ability to decode metabolic signals, K(ATP) channels set membrane excitability to match demand for homeostatic maintenance. This new paradigm in the operation of an ion channel multimer is essential in providing the basis for K(ATP) channel function in the cardiac cell, and for understanding genetic defects associated with life-threatening diseases that result from the inability of the channel complex to optimally fulfill its physiological role.
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PMID:ATP-sensitive K+ channel channel/enzyme multimer: metabolic gating in the heart. 1591 Aug 74

The lumen of the inner ear has an unusually low concentration of endolymphatic Na+, which is important for transduction processes. We have recently shown that glucocorticoid receptors (GR) stimulate absorption of Na+ by semicircular canal duct (SCCD) epithelia. In the present study, we sought to determine the presence of genes involved in the control of the amiloride-sensitive Na+ transport pathway in rat SCCD epithelia and whether their level of expression was regulated by glucocorticoids using quantitative real-time RT-PCR. Transcripts were present for alpha-, beta-, and gamma-subunits of the epithelial sodium channel (ENaC); the alpha1-, alpha3-, beta1-, and beta3-isoforms of Na+-K+-ATPase; inwardly rectifying potassium channels [IC50 of short circuit current (Isc) for Ba2+: 210 microM] Kir2.1, Kir2.2, Kir2.3, Kir2.4, Kir3.1, Kir3.3, Kir4.1, Kir4.2, Kir5.1, and Kir7.1; sulfonyl urea receptor 1 (SUR1); GR; mineralocorticoid receptor (MR); 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2; serum- and glucocorticoid-regulated kinase 1 (Sgk1); and neural precursor cell-expressed developmentally downregulated 4-2 (Nedd4-2). On the other hand, transcripts for the alpha4-subunit of Na+-K+-ATPase, Kir1.1, Kir3.2, Kir3.4, Kir6.1, Kir6.2, and SUR2 were found to be absent, and Isc was not inhibited by glibenclamide. Dexamethasone (100 nM for 24 h) not only upregulated the transcript expression of alpha-ENaC (approximately 4-fold), beta2-subunit (approximately 2-fold) and beta3-subunit (approximately 8-fold) of Na+-K+-ATPase, Kir2.1 (approximately 5-fold), Kir2.2 (approximately 9-fold), Kir2.4 (approximately 3-fold), Kir3.1 (approximately 3- fold), Kir3.3 (approximately 2-fold), Kir4.2 (approximately 3-fold), Kir7.1 (approximately 2-fold), Sgk1 (approximately 4-fold), and Nedd4-2 (approximately 2-fold) but also downregulated GR (approximately 3-fold) and 11beta-HSD1 (approximately 2-fold). Expression of GR and 11beta-HSD1 was higher than MR and 11beta-HSD2 in the absence of dexamethasone. Dexamethasone altered transcript expression levels (alpha-ENaC and Sgk1) by activation of GR but not MR. Proteins were present for the alpha-, beta-, and gamma-subunits of ENaC and Sgk1, and expression of alpha- and gamma-ENaC was upregulated by dexamethasone. These findings are consistent with the genomic stimulation by glucocorticoids of Na+ absorption by SCCD and provide an understanding of the therapeutic action of glucocorticoids in the treatment of Meniere's disease.
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PMID:Glucocorticoid regulation of genes in the amiloride-sensitive sodium transport pathway by semicircular canal duct epithelium of neonatal rat. 1626 2

The sulfonylurea receptors (SURs) ABCC8/SUR1 and ABCC9/SUR2 are members of the C-branch of the transport adenosine triphosphatase superfamily. Unlike their brethren, the SURs have no identified transport function; instead, evolution has matched these molecules with K(+) selective pores, either K(IR)6.1/KCNJ8 or K(IR)6.2/KCNJ11, to assemble adenosine triphosphate (ATP)-sensitive K(+) channels found in endocrine cells, neurons, and both smooth and striated muscle. Adenine nucleotides, the major regulators of ATP-sensitive K(+) (K(ATP)) channel activity, exert a dual action. Nucleotide binding to the pore reduces the activity or channel open probability, whereas Mg-nucleotide binding and/or hydrolysis in the nucleotide-binding domains of SUR antagonize this inhibitory action to stimulate channel openings. Mutations in either subunit can alter this balance and, in the case of the SUR1/KIR6.2 channels found in neurons and insulin-secreting pancreatic beta cells, are the cause of monogenic forms of hyperinsulinemic hypoglycemia and neonatal diabetes. Additionally, the subtle dysregulation of K(ATP) channel activity by a K(IR)6.2 polymorphism has been suggested as a predisposing factor in type 2 diabetes mellitus. Studies on K(ATP) channel null mice are clarifying the roles of these metabolically sensitive channels in a variety of tissues.
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PMID:ABCC8 and ABCC9: ABC transporters that regulate K+ channels. 1689 43

To investigate the mechanisms regulating excitation-metabolic coupling in rabbit epicardial, midmyocardial, and endocardial ventricular myocytes we extended the LabHEART model (Puglisi JL and Bers DM. Am J Physiol Cell Physiol 281: C2049-C2060, 2001). We incorporated equations for Ca(2+) and Mg(2+) buffering by ATP and ADP, equations for nucleotide regulation of ATP-sensitive K(+) channel and L-type Ca(2+) channel, Na(+)-K(+)-ATPase, and sarcolemmal and sarcoplasmic Ca(2+)-ATPases, and equations describing the basic pathways (creatine and adenylate kinase reactions) known to communicate the flux changes generated by intracellular ATPases. Under normal conditions and during 20 min of ischemia, the three regions were characterized by different I(Na), I(to), I(Kr), I(Ks), and I(Kp) channel properties. The results indicate that the ATP-sensitive K(+) channel is activated by the smallest reduction in ATP in epicardial cells and largest in endocardial cells when cytosolic ADP, AMP, PCr, Cr, P(i), total Mg(2+), Na(+), K(+), Ca(2+), and pH diastolic levels are normal. The model predicts that only K(ATP) ionophore (Kir6.2 subunit) and not the regulatory subunit (SUR2A) might differ from endocardium to epicardium. The analysis suggests that during ischemia, the inhomogeneous accumulation of the metabolites in the tissue sublayers may alter in a very irregular manner the K(ATP) channel opening through metabolic interactions with the endogenous PI cascade (PIP(2), PIP) that in turn may cause differential action potential shortening among the ventricular myocyte subtypes. The model predictions are in qualitative agreement with experimental data measured under normal and ischemic conditions in rabbit ventricular myocytes.
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PMID:Modeling transmural heterogeneity of K(ATP) current in rabbit ventricular myocytes. 1732 4

The ATP-sensitive potassium (K(ATP)) channel couples glucose metabolism to insulin secretion in pancreatic beta-cells. It comprises regulatory sulfonylurea receptor 1 and pore-forming Kir6.2 subunits. Binding and/or hydrolysis of Mg-nucleotides at the nucleotide-binding domains of sulfonylurea receptor 1 stimulates channel opening and leads to membrane hyperpolarization and inhibition of insulin secretion. We report here the first purification and functional characterization of sulfonylurea receptor 1. We also compared the ATPase activity of sulfonylurea receptor 1 with that of the isolated nucleotide-binding domains (fused to maltose-binding protein to improve solubility). Electron microscopy showed that nucleotide-binding domains purified as ring-like complexes corresponding to approximately 8 momomers. The ATPase activities expressed as maximal turnover rate [in nmol P(i).s(-1).(nmol protein)(-1)] were 0.03, 0.03, 0.13 and 0.08 for sulfonylurea receptor 1, nucleotide-binding domain 1, nucleotide-binding domain 2 and a mixture of nucleotide-binding domain 1 and nucleotide-binding domain 2, respectively. Corresponding K(m) values (in mm) were 0.1, 0.6, 0.65 and 0.56, respectively. Thus sulfonylurea receptor 1 has a lower K(m) than either of the isolated nucleotide-binding domains, and a lower maximal turnover rate than nucleotide-binding domain 2. Similar results were found with GTP, but the K(m) values were lower. Mutation of the Walker A lysine in nucleotide-binding domain 1 (K719A) or nucleotide-binding domain 2 (K1385M) inhibited the ATPase activity of sulfonylurea receptor 1 by 60% and 80%, respectively. Beryllium fluoride (K(i) 16 microm), but not MgADP, inhibited the ATPase activity of sulfonylurea receptor 1. In contrast, both MgADP and beryllium fluoride inhibited the ATPase activity of the nucleotide-binding domains. These data demonstrate that the ATPase activity of sulfonylurea receptor 1 differs from that of the isolated nucleotide-binding domains, suggesting that the transmembrane domains may influence the activity of the protein.
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PMID:Studies of the ATPase activity of the ABC protein SUR1. 1756 60

Gain-of-function mutations in the genes encoding the ATP-sensitive potassium (K(ATP)) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) are a common cause of neonatal diabetes mellitus. Here we investigate the molecular mechanism by which two heterozygous mutations in the second nucleotide-binding domain (NBD2) of SUR1 (R1380L and R1380C) separately cause neonatal diabetes. SUR1 is a channel regulator that modulates the gating of the pore formed by Kir6.2. K(ATP) channel activity is inhibited by ATP binding to Kir6.2 but is stimulated by MgADP binding, or by MgATP binding and hydrolysis, at the NBDs of SUR1. Functional analysis of purified NBD2 showed that each mutation enhances MgATP hydrolysis by purified isolated fusion proteins of maltose-binding protein and NBD2. Inhibition of ATP hydrolysis by MgADP was unaffected by mutation of R1380, but inhibition by beryllium fluoride (which traps the ATPase cycle in the prehydrolytic state) was reduced. MgADP-dependent activation of K(ATP) channel activity was unaffected. These data suggest that the R1380L and R1380C mutations enhance the off-rate of P(i), thereby enhancing the hydrolytic rate. Molecular modeling studies supported this idea. Because mutant channels were inhibited less strongly by MgATP, this would increase K(ATP) currents in pancreatic beta cells, thus reducing insulin secretion and producing diabetes.
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PMID:Increased ATPase activity produced by mutations at arginine-1380 in nucleotide-binding domain 2 of ABCC8 causes neonatal diabetes. 1802 64

Nucleotide binding domains (NBDs) secure ATP-binding cassette (ABC) transporter function. Distinct from traditional ABC transporters, ABCC9-encoded sulfonylurea receptors (SUR2A) form, with Kir6.2 potassium channels, ATP-sensitive K+ (K ATP) channel complexes. SUR2A contains ATPase activity harbored within NBD2 and, to a lesser degree, NBD1, with catalytically driven conformations exerting determinate linkage on the Kir6.2 channel pore. While homodomain interactions typify NBDs of conventional ABC transporters, heterodomain NBD interactions and their functional consequence have not been resolved for the atypical SUR2A protein. Here, nanoscale protein topography mapped assembly of monodisperse purified recombinant SUR2A NBD1/NBD2 domains, precharacterized by dynamic light scattering. Heterodomain interaction produced conformational rearrangements inferred by secondary structural change in circular dichroism, and validated by atomic force and transmission electron microscopy. Physical engagement of NBD1 with NBD2 translated into enhanced intrinsic ATPase activity. Molecular modeling delineated a complemental asymmetry of NBD1/NBD2 ATP-binding sites. Mutation in the predicted catalytic base residue, D834E of NBD1, altered NBD1 ATPase activity disrupting potentiation of catalytic behavior in the NBD1/NBD2 interactome. Thus, NBD1/NBD2 assembly, resolved by a panel of proteomic approaches, provides a molecular substrate that determines the optimal catalytic activity in SUR2A, establishing a paradigm for the structure-function relationship within the K ATP channel complex.
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PMID:Interaction of asymmetric ABCC9-encoded nucleotide binding domains determines KATP channel SUR2A catalytic activity. 1831 11

Activating mutations in the pore-forming Kir6.2 (KCNJ11) and regulatory sulphonylurea receptor SUR1 (ABCC8) subunits of the K(ATP) channel are a common cause of transient neonatal diabetes mellitus (TNDM). We identified a new TNDM mutation (R826W) in the first nucleotide-binding domain (NBD1) of SUR1. The mutation was found in a region that heterodimerizes with NBD2 to form catalytic site 2. Functional analysis showed that this mutation decreases MgATP hydrolysis by purified maltose-binding protein MBP-NBD1 fusion proteins. Inhibition of ATP hydrolysis by MgADP or BeF was not changed. The results indicate that the ATPase cycle lingers in the post-hydrolytic MgADP.P(i)-bound state, which is associated with channel activation. The extent of MgADP-dependent activation of K(ATP) channel activity was unaffected by the R826W mutation, but the time course of deactivation was slowed. Channel inhibition by MgATP was reduced, leading to an increase in resting whole-cell currents. In pancreatic beta cells, this would lead to less insulin secretion and thereby diabetes.
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PMID:A mutation (R826W) in nucleotide-binding domain 1 of ABCC8 reduces ATPase activity and causes transient neonatal diabetes. 1849 52

SUR1 is an ATP-binding cassette (ABC) transporter with a novel function. In contrast to other ABC proteins, it serves as the regulatory subunit of an ion channel. The ATP-sensitive (KATP) channel is an octameric complex of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits, and it links cell metabolism to electrical activity in many cell types. ATPase activity at the nucleotide-binding domains of SUR results in an increase in KATP channel open probability. Conversely, ATP binding to Kir6.2 closes the channel. Metabolic regulation is achieved by the balance between these two opposing effects. Precisely how SUR1 talks to Kir6.2 remains unclear, but recent studies have identified some residues and domains that are involved in both physical and functional interactions between the two proteins. The importance of these interactions is exemplified by the fact that impaired regulation of Kir6.2 by SUR1 results in human disease, with loss-of-function SUR1 mutations causing congenital hyperinsulinism and gain-of-function SUR1 mutations leading to neonatal diabetes. This paper reviews recent data on the regulation of Kir6.2 by SUR1 and considers the molecular mechanisms by which SUR1 mutations produce disease.
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PMID:Review. SUR1: a unique ATP-binding cassette protein that functions as an ion channel regulator. 1899 Jun 70

Unusually among ATP-binding cassette proteins, the sulfonylurea receptor (SUR) acts as a channel regulator. ATP-sensitive potassium channels are octameric complexes composed of four pore-forming Kir6.2 subunits and four regulatory SUR subunits. Two different genes encode SUR1 (ABCC8) and SUR2 (ABCC9), with the latter being differentially spliced to give SUR2A and SUR2B, which differ only in their C-terminal 42 amino acids. ATP-sensitive potassium channels containing these different SUR2 isoforms are differentially modulated by MgATP, with Kir6.2/SUR2B being activated more than Kir6.2/SUR2A. We show here that purified SUR2B has a lower ATPase activity and a 10-fold lower K(m) for MgATP than SUR2A. Similarly, the isolated nucleotide-binding domain (NBD) 2 of SUR2B was less active than that of SUR2A. We further found that the NBDs of SUR2B interact, and that the activity of full-length SUR cannot be predicted from that of either the isolated NBDs or NBD mixtures. Notably, deletion of the last 42 amino acids from NBD2 of SUR2 resulted in ATPase activity resembling that of NBD2 of SUR2A rather than that of NBD2 of SUR2B: this might indicate that these amino acids are responsible for the lower ATPase activity of SUR2B and the isolated NBD2 of SUR2B. We suggest that the lower ATPase activity of SUR2B may result in enhanced duration of the MgADP-bound state, leading to channel activation.
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PMID:The ATPase activities of sulfonylurea receptor 2A and sulfonylurea receptor 2B are influenced by the C-terminal 42 amino acids. 2055 99


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