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

---

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

Increased hepatic glucose production is responsible for fasting hyperglycemia in type II diabetes. Insulin resistance is the key in this process because of the inability of insulin to suppress hepatic glucose production, thereby allowing an unopposed glucagon effect. Glyburide, one of the second-generation sulfonylureas, decreases glucose production and enhances insulin action in the liver. Available data suggest that glyburide: (1) enhances glycogen synthesis in the liver by increasing glycogen synthase; (2) inhibits glycogenolysis by decreasing phosphorylase alpha activity; and (3) decreases gluconeogenesis and stimulates glycolysis by decreasing A-kinase activity, which results in increased fructose 2,6-bisphosphate, one of the key regulators of carbohydrate metabolism in the liver. The effect of glyburide on the insulin-signaling mechanism(s) is distal to the insulin binding site of the alpha-subunit of the insulin receptor and the tyrosine kinase activation site of the beta-subunit.
...
PMID:Effects of glyburide on carbohydrate metabolism and insulin action in the liver. 211 86

The possible role of protein kinase c in regulating the electrical events in the B-cell plasma membrane was examined by using the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), a known activator of this enzyme. TPA has been found to enhance glucose- and sulfonylurea-induced insulin secretion with little or no effect on the fluxes of 86Rb+ or 45Ca2+ across the plasma membrane. TPA, 0.2 microM, did not influence the membrane potential from 0 to 5.6 mM glucose but increased by two- to threefold the fraction of the plateau phase of the oscillatory electrical activity induced by 7.0-11.1 mM glucose. This effect of TPA was completely blocked by 0.5 mM spermidine, an inhibitor of protein kinase c. However, spermidine had no influence on the electrical activity elicited by glucose alone. Glyburide, 10 nM, initiated slow depolarization and constant spike activity after about 18 and 25 min, respectively. TPA or 2.8 mM glucose reduced the lag period for glyburide to elicit an electrical response by about 75%. The duration of the spikes was increased two- to threefold by the presence of glucose or TPA with glyburide. There were also characteristic differences in the shape of the spikes under each experimental condition. Spermidine inhibited the influence of glucose, but not TPA, on the glyburide-induced electrical response. These results indicate that TPA may influence stimulant-induced electrical events via protein kinase c or by directly altering the ionic permeability of the plasma membrane.
...
PMID:Action of a phorbol ester on B-cells: potentiation of stimulant-induced electrical activity. 315 14

The role of ATP-sensitive K+ channels (KATP) in ischemia and reperfusion (I/R) was studied in isolated rat lungs. I/R produced a sixfold increase in endothelial permeability as measured by the capillary filtration coefficient. Cromakalim (10 microM) given at 46 min after reperfusion reversed the filtration coefficient increase. This effect was not blocked by either a protein kinase A inhibitor (adenosine-3',5'-cyclic monophosphothioate; 100 microM) or an adenosine antagonist [8-(p-sulfophenyl)-theophylline; 20 microM]. Cromakalim given before ischemia or at the beginning of reperfusion protected the endothelial barrier from injury. Glibenclamide (500 microM) given before the ischemic period, at the beginning of reperfusion, or 46 min after reperfusion did not alter the changes in microvascular permeability produced by I/R. Glibenclamide blocked the ability of cromakalim to reverse endothelial damage but not the ability of either isoproterenol (10 microM) or an adenosine A2-receptor agonist, CGS-21680 (300 nM). We conclude that opening of KATP channels does not produce endothelial injury in I/R. The activation of KATP channels can both protect against and reverse the endothelial damage associated with I/R. This novel mechanism(s) is independent from known pathways that employ cAMP-protein kinase system and adenosine.
...
PMID:ATP-sensitive K+ channels are not involved in ischemia-reperfusion lung endothelial injury. 759 17

Stimulation of the beta-adrenoceptor activates a time-independent Cl- conductance that is known to be regulated via phosphorylation by cAMP-dependent protein kinase in guinea pig ventricular myocytes. Since epithelial cystic fibrosis transmembrane conductance regulator Cl- channels are known to be sensitive to an antidiabetic sulfonylurea, glibenclamide, we tested whether the drug modulates cardiac cAMP-activated Cl- conductance. Bath application of isoproterenol (1 mumol/L, n = 11) or forskolin (1 mumol/L, n = 17) or the intracellular application of cAMP (1 mmol/L, n = 9) activated whole-cell Cl- currents recorded from single myocytes at 36 degrees C. External glibenclamide (> or = 10 mumol/L, n = 26) inhibited the Cl- current induced by either of the stimulants in a concentration-dependent manner. The half-maximal inhibition concentration (IC50) of glibenclamide and the Hill coefficient were 24.5 to 37.9 mumol/L and 1.6 to 2.2, respectively. During current-clamp experiments, forskolin was found to shorten the action potential significantly (250 +/- 45 to 201 +/- 52 milliseconds, P < .05) in 7 of 11 cells tested. Glibenclamide antagonized the forskolin-induced shortening (to 243 +/- 54 milliseconds, n = 7, P < .05). Intracellular administration of sodium orthovanadate (0.5 to approximately 1 mmol/L, n = 6) brought about persistent activation of Cl- current after brief bath application of forskolin. This Cl- current was not affected by H-89 (100 mumol/L, n = 3), a specific inhibitor of cAMP-dependent protein kinase, and was suppressed by glibenclamide similarly, with an IC50 of 29.7 mumol/L.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Glibenclamide, an ATP-sensitive K+ channel blocker, inhibits cardiac cAMP-activated Cl- conductance. 761 25

Follicular cells from Xenopus oocytes offer a particularly interesting system to study ATP-sensitive K+ channels (KATP channels). In these cells, as in many other cell types, glibenclamide is a classical blocker of KATP channels. Metabolic inhibition with dinitrophenol (DNP) converts this inhibitory effect into an activation. Follicular cells treated with DNP keep their sensitivity to the KATP channel opener P1060, but this opening effect becomes insensitive to glibenclamide inhibition. Glibenclamide activation of KATP channels in DNP-treated follicular cells occurs with an EC50 of 3 microM. Glibenclamide activation is antagonized by blockers of KATP channels that do not belong to the sulfonylurea family, such as U-37883A, tedisamil, and LH 35. Other sulfonylureas display the same activating behavior as does glibenclamide in DNP-treated cells. Two of the properties of KATP channels in follicular cells are activation by cAMP through protein kinase A and inhibition by muscarinic effectors through protein kinase C activation. The stimulating effects of cAMP and glibenclamide in DNP-treated cells seem to be synergistic as are the cAMP and P1060 effects in control follicular cells. Glibenclamide-activated KATP channels in DNP-treated cells (conductance of 15 pS) are also inhibited by acetylcholine and by phorbol esters. The internal acidosis produced by metabolic exhaustion with DNP appears to be the key element in the conversion of glibenclamide from a blocker to an activator of KATP channels.
...
PMID:Glibenclamide opens ATP-sensitive potassium channels in Xenopus oocyte follicular cells during metabolic stress. 770 Feb 56

Whole cell and single-channel patch-clamp techniques were used to identify and characterize the Cl- currents responsible for adenosine 3',5'-cyclic monophosphate (cAMP)-mediated Cl- secretion in the rectal gland of the spiny dogfish (Squalus acanthias). During whole cell recordings, in cultured rectal gland cells forskolin (10 microM) and 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate (400 microM) stimulated a 28-fold increase in Cl- conductance (n = 10). This cAMP-activated conductance pathway had a linear current-voltage (I-V) relationship that was time and voltage independent. Substitution of 235 meq Cl- with I- in the bath inhibited the cAMP-activated current at both positive and negative voltages (64%). Glibenclamide (60 microM) abolished the cAMP-stimulated current, and its effect was irreversible (n = 3). During cell-attached recording, increased cellular cAMP activated single Cl- channels in nine previously quiet patches. These channels had a linear I-V relationship with an average single-channel conductance of 5.1 +/- 0.2 pS (n = 6). Similar properties were observed in excised inside-out patches, permitting further characterization of the single-channel properties. Excised quiescent patches could be activated by the addition of ATP and protein kinase A. Replacing bath Cl- with I- inhibited both inward and outward currents (n = 3). In three inside-out patches, glibenclamide (300 microM) reversibly reduced open probability by 74%, with no effect on single-channel current amplitude. Similar results were obtained in four outside-out recordings. These results suggest that increased cellular cAMP in dogfish rectal gland activates a small linear Cl- channel that resembles human cystic fibrosis transmembrane conductance regulator in its biophysical and pharmacological properties.
...
PMID:cAMP-activated Cl- channels in primary cultures of spiny dogfish (Squalus acanthias) rectal gland. 784 Jan 62

Calcium tolerant rabbit cardiomyocytes, isolated by collagenase perfusion, were preincubated for varying periods of time followed by resuspension in fresh media and centrifugation into an ischaemic pellet with restricted extracellular fluid. Pellets were incubated for 240 min under oil at 37 degrees C to mimic severe ischaemia. Time to onset of ischaemic contracture (rod to square transformation) and trypan blue permeability following resuspension in 85 mOSM media were monitored at sequential times. The protocol of Series 1 was a 5-10 min pre-incubation, immediately followed by ischaemic pelleting. Preincubation with pinacidil (50 microM) protected cells from ischaemic insult, but pinacidil added only into the ischaemic pellet did not protect. Protection was abolished by the protein kinase (PKC) inhibitors chelerythrine (10 microM) added with pinacidil and calphostin C (200nM) added only into the ischaemic pellet. Neither PKC inhibitor had an effect on injury of untreated ischaemic myocytes (data not shown). Series 2-5 were preconditioning protocols with a 10 min intervention period, followed by a 30 min oxygenated drug-free period, prior to ischaemic pelleting. In series 2 pinacidil protected cells from ischaemic insult and this protection was abolished when glyburide (10 microM) was present during preincubation, or during post-incubation and ischaemia. Glyburide only partially inhibited the protection when glyburide was added only into the ischaemic pellet. In Series 3, 8-sulfophenyltheophyline (SPT)(100 microM) or adenosine deaminase during preincubation, or SPT only added into the ischaemic pellet abolished pinacidil's protection. In Series 4, cardiomyocytes were ischaemically preconditioned by pelleting for 10 min followed by 30 min reoxygenation. Glyburide during initial ischaemic blocked protection, but when added during post incubation and into the final pellet protection was not reduced. In Series 5 8-cyclopentyl-1,3,dipropylxanthine (DPCPX) (10 microM) added into the final pellet abolished protection by pinacidil, but not protection following ischaemic preconditioning. In contrast to pinacidil, ischaemically preconditioned cells maintain protection in the presence of glyburide, indicating that: (1) pinacidil does not exactly mimic preconditioning and (2) ischaemically preconditioned cells do not require opened K+ATP channels for protection, although they appear to be important during initiation of the preconditioned state. It is hypothesized that pinacidil opening of K+ channels may facilitate induction of preconditioning.
...
PMID:Potassium channels and preconditioning of isolated rabbit cardiomyocytes: effects of glyburide and pinacidil. 852 37

The mechanism by which the endogenous vasodilator adenosine causes ATP-sensitive potassium (KATP) channels in arterial smooth muscle to open was investigated by the whole-cell patch-clamp technique. Adenosine induced voltage-independent, potassium-selective currents, which were inhibited by glibenclamide, a blocker of KATP currents. Glibenclamide-sensitive currents were also activated by the selective adenosine A2-receptor agonist 2-p-(2-carboxethyl)-phenethylamino-5'-N- ethylcarboxamidoadenosine hydrochloride (CGS-21680), whereas 2-chloro-N6-cyclopentyladenosine (CCPA), a selective adenosine A1-receptor agonist, failed to induce potassium currents. Glibenclamide-sensitive currents induced by adenosine and CGS-21680 were largely reduced by blockers of the cAMP-dependent protein kinase (Rp-cAMP[S], H-89, protein kinase A inhibitor peptide). Therefore, we conclude that adenosine can activate KATP currents in arterial smooth muscle through the following pathway: (i) Adenosine stimulates A2 receptors, which activates adenylyl cyclase; (ii) the resulting increase intracellular cAMP stimulates protein kinase A, which, probably through a phosphorylation step, opens KATP channels.
...
PMID:Adenosine activates ATP-sensitive potassium channels in arterial myocytes via A2 receptors and cAMP-dependent protein kinase. 861 17

1. The aim of this study was to assess whether agents that interfere with the intracellular actions of cAMP and activation of protein kinase A (PKA) prevent the inhibitory action of human alpha-calcitonin gene-related peptide (CGRP) in the guinea-pig ureter smooth muscle. The action of CGRP was compared to that of the K+ channel opener, cromakalim, and the adenylyl cyclase activator, forskolin, toward electrical field stimulation- (EFS) induced myogenic twitch contractions of the ureter. To further verify the role of cAMP in the action of CGRP, we also studied the effect of stable cAMP analogues and of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). 2. Maximally effective concentrations of CGRP (0.1 microM) or forskolin (10 microM) produced a transient suppression of twitches. Cromakalim (3 microM) likewise produced a prompt suppression of twitches that in most cases exceeded 15 min. The early suppressant effect of CGRP or forskolin was inhibited by 1 or 10 microM glibenclamide; about 30% of the effect of CGRP was glibenclamide-resistant. The effect of cromakalim was totally suppressed by glibenclamide. 3. The inhibitory effect of CGRP was concentration-dependently reduced by low concentrations of barium chloride (IC50 63 microM), which blocked with similar potency the inhibitory action of cromakalim (IC50 60 microM). Glibenclamide (10 nM-10 microM) concentration-dependently inhibited the effect of CGRP and cromakalim with IC50S of 0.13 and 0.72 microM, respectively. 4. The cAMP analogues dibutyrye-cAMP (1-3 mM), 8-(4-chlorophenylthio)cAMP (0.3-1 mM) and Sp-cAMP monophosphothioate (0.1-0.3 mM) were either ineffective or poorly effective in inhibiting twitches. The cGMP analog, 8Br-cGMP (100-300 microM) produced a slowly developing, glibenclamide (1 microM)-resistant partial inhibition (25-30%) of twitches. 5. IBMX (1-300 microM) produced a concentration-dependent inhibition of twitches (EC50 16 microM). IBMX (100 microM) produced a large (peak 91%) and transient inhibition: glibenclamide (1 microM) blocked the early peak of the inhibitory action of IBMX, similar to the effect observed toward CGRP and forskolin.
...
PMID:Role of cyclic AMP and protein kinase A in K+ channel activation by calcitonin gene-related peptide (CGRP) in the guinea-pig ureter. 874 80

We aimed at studying the mechanism(s) of the inhibitory effect exerted by calcitonin gene-related peptide (CGRP) on the spontaneous activity of the guinea-pig isolated renal pelvis. In organ bath experiments, CGRP (1-100 nM) produced a concentration-dependent (EC50 8 nM) partial inhibition (Emax about 35% inhibition of motility index) of spontaneous contractions. The potassium (K) channel opener, cromakalim (3-10 microM) promptly suppressed the spontaneous contractions in a glibenclamide-(10 microM) sensitive manner. Glibenclamide (10 microM) did not affect the inhibitory action of CGRP. The calcium (Ca) channel agonist, Bay K 8644 (1 microM), markedly enhanced the spontaneous activity of the renal pelvis and reduced the inhibitory effect of CGRP. The protein kinase A inhibitors Rp-cAMPS (300 microM), H8 (100 microM) and H89 (10 microM), and the blockers of intracellular Ca handling by sarcoplasmic reticulum, ryanodine (100 microM) and thapsigargin (1 microM) did not affect the response to CGRP. The response to CGRP was likewise unaffected by the nitric oxide synthase inhibitor, L-nitroarginine (30 microM) and by the protein kinase G inhibitor, KT5823 (3 microM). Furthermore, the inhibitory action of CGRP was not modified by lowering the extracellular concentration of K (from 5.9 to 1.2 mM) nor by increasing (from 2.5 to 3.75 mM) or decreasing (from 2.5 to 0.25 mM) the extracellular Ca concentration. Replacement of 80% glucose with 2-deoxyglucose (2-DOG) reduced the amplitude of spontaneous contractions, both in the absence and presence of 10 microM glibenclamide. In the presence of 2-DOG, the inhibitory action of CGRP was enhanced at a similar extent, either in the absence or presence of glibenclamide. In sucrose gap, the effect of CGRP (0.1 microM for 5 min) was separately analyzed in the proximal (close to the kidney) and distal (close to the ureter) regions of the renal pelvis. Both preparations discharged spontaneous (pacemaker) action potentials having different shape, duration and frequently. CGRP had no effect on pacemaker potentials in the proximal renal pelvis while producing about 30% reduction of the frequency of pacemaker potentials and motility index in the distal renal pelvis. Cromakalim (3 microM) abolished pacemaker potentials in both regions of the renal pelvis. In conjunction with the results of previous studies in the guinea-pig ureter, the present findings document the existence of remarkable regional differences in the effector mechanisms initiated by CGRP receptor occupancy in the guinea-pig pyeloureteral tract. CGRP appears to be inherently unable to activate glibenclamide-sensitive K channels in the guinea-pig renal pelvis, a mechanism which is central for its ability to suppress latent pacemakers in the ureter. Within the renal pelvis, the sensitivity to the inhibitory effect of CGRP appears in the more distal region, from which an 'ureter-like' action potential is recorded.
...
PMID:CGRP inhibition of electromechanical coupling in the guinea-pig isolated renal pelvis. 875 Oct 82


1 2 3 4 Next >>

---