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 purified receptor for calcium channel blockers (CaCB-receptor) from rabbit skeletal muscle contains three polypeptides within a molecular mass of 165, 55, and 32 kDa. cAMP-dependent protein kinase was shown to phosphorylate preferentially the 165-kDa protein. The major phosphorylation site was identified and compared with the recently published primary sequence of the CaCB-receptor. It is concluded that serine 687 is the phosphorylation site. Phosphorylation of serine 687 may regulate the open-state probability of the CaCB-receptor.
J Cardiovasc Pharmacol 1988
PMID:Phosphorylation of the purified CaCB-receptor. 246 77

Smooth muscle cells contain two distinct Ca2+-transport ATpases with a different subcellular localization. The plasmalemmal Ca2+ pump has a relative molecular weight (Mr) of 140k and its phospho-intermediate level is increased by La3+. Its resemblance to the erythrocyte Ca2+ pump is further confirmed by its calmodulin-binding capacity and its antigenic properties. A 100k Ca2+-transport ATPase is localized in the endoplasmic reticulum. Its phospho-intermediate level is decreased by La3+, and it is antigenically related to the cardiac sarcoplasmic reticulum Ca2+-transport ATPase. These two different Ca2+-transport ATPases are present in both visceral and vascular smooth muscle, but tissue- and species-dependent differences in their relative amount have been observed. The endoplasmic-reticulum Ca2+-transport ATPase is regulated via phospholamban. Phosphorylation of this regulatory protein by cAMP-dependent as well as by cGMP-dependent protein kinase stimulates the endoplasmic-reticulum Ca2+ pump. The activity of the plasmalemmal Ca2+-transport ATPase can be modulated by calmodulin, negatively charged phospholipids, and by receptor-binding agonists. cGMP-dependent protein kinase also exerts a stimulatory effect on the plasmalemmal Ca2+ pump, but this effect is not mediated via a direct phosphorylation of the Ca2+ pump.
J Cardiovasc Pharmacol 1988
PMID:The (Ca2+-Mg2+)-ATPases of the plasma membrane and of the endoplasmic reticulum in smooth muscle cells and their regulation. 246 79

The purpose of the present study was to examine the interrelationships among phosphodiesterase (PDE) isozyme inhibition, cAMP formation, activation of cAMP-dependent protein kinase (cAPK), and positive inotropy in isolated guinea pig cardiac muscle mediated by the cardiotonic/vasodilator agent, milrinone. Milrinone was a potent and selective inhibitor of the "low Km" cAMP PDE isozyme (peak III) isolated by diethylaminoethyl ether cellulose chromatography, with IC50 values of 0.7 microM for peak III PDE and 100 microM for peak I PDE. In isolated papillary muscles frozen at peak inotropic responses, positive and significant correlations were evident between isometric force development as a function of cAMP content (r = 0.72, p less than 0.05) or cAPK activity ratio, an index of activation of cAPK (r = 0.79, p less than 0.001), for concentrations of milrinone from 0.1-1000 microM. Similar correlations were evident in muscles frozen at peak inotropic responses for the beta-adrenoreceptor agonist isoproterenol (r = 0.96, p less than 0.001; r = 0.98, p less than 0.001, respectively), but not for ouabain or Bay K-8644. The temporal sequence of these events was also quantitated for concentrations of milrinone (100 microM) and isoproterenol (3 nM) that produced approximately a 100% increase in isometric force. Whereas early time interval of force development (30 s, 1 min, isoproterenol; 30 s milrinone) were not accompanied by significant increases in either cAMP content or cAPK activity ratio, peak increases in force development for both isoproterenol (2 min) and milrinone (1 min) were related to peak increases in cAPK activity ratios. In summary, these results show that significant increases in cAMP content or cAPK activation are correlated with positive inotropy in isolated guinea pig papillary muscles with milrinone. These correlations occur at concentrations of milrinone that inhibit cardiac PDE isozymes and are similar to the known cAMP-dependent cardiostimulant isoproterenol. These data support the hypothesis that selective PDE isozyme inhibition is a mechanism by which milrinone effects positive inotropy.
J Cardiovasc Pharmacol 1989 Apr
PMID:Phosphodiesterase isozyme inhibition, activation of the cAMP system, and positive inotropy mediated by milrinone in isolated guinea pig cardiac muscle. 247 Sep 89

The possible involvement of three different second-messenger systems, namely cyclic AMP/protein kinase (PK)-A, cyclic GMP/PK-G, and diacylglycerol (DG)/PK-C systems, in the perivascular nerve terminals of guinea pig mesenteric artery was examined by intracellular microelectrode recording. Excitatory junction potentials (EJPs) were evoked by perivascular nerve stimulation. Isoproterenol (0.1 microM) enhanced the EJP amplitude without modifying the passive membrane properties of the vascular smooth muscle (VSM) cells. The facilitatory effect of isoproterenol on EJP amplitude was completely abolished by beta-adrenergic blockade (0.3 microM propranolol). Forskolin (activator of adenylate cyclase) also augmented the EJP amplitude in a concentration-dependent manner (EC50 congruent to 10 microM), without affecting the passive membrane properties of the VSM cells. In addition, forskolin (1-10 mM) markedly potentiated the isoproterenol-induced stimulation of EJP amplitude (EC50 congruent to 2 microM). A permeant analogue of cyclic AMP, 8-bromo-cyclic AMP (0.1 and 1 mM), enhanced the EJP amplitude, thus mimicking the effects of isoproterenol and forskolin. 8-Bromo-cyclic AMP had no effect on the resting potential or current-voltage relationship of the VSM cells, thus suggesting that the membrane properties of the VSM cells were not altered. 8-Bromo-cyclic GMP (1 mM) also augmented the EJP amplitude, but its facilitatory effect was weaker than that of 8-bromo-cyclic AMP. 8-Bromo-cyclic GMP hyperpolarized the VSM membrane by 4 mV and decreased the input resistance, presumably due to an increase in K+ conductance. Phorbol-12-myristate-13-acetate (PMA, 30-300 nM), a direct activator of PK-C, significantly enhanced the EJP amplitude after 40 min in a concentration-dependent manner, without affecting the resting potential of the VSM cells. From these results, we suggest that cyclic AMP/PK-A, cyclic GMP/PK-G, and DG/PK-C systems might be involved in regulation of the release of neurotransmitter in the perivascular nerve terminals. However, the possibility of some action on the postsynaptic VSM cell cannot be excluded.
J Cardiovasc Pharmacol 1989 Jun
PMID:Cyclic nucleotide regulation of neurotransmission in guinea pig mesenteric artery. 248 77

A study was performed to determine whether the proteins phosphorylated by cAMP dependent and calmodulin dependent protein kinase in vascular smooth muscle membrane fractions represent integral membrane proteins or are tightly associated cytoskeletal proteins. In the unextracted microsomal fraction cAMP dependent protein kinase phosphorylated proteins of 240K, 105K, and 48K daltons. Similarly, calmodulin dependent protein kinase phosphorylated 65K, 60K, 48K, and 20K dalton bands. The 48K dalton band represented a major protein in the microsomal fraction, and it was a common substrate for both cAMP dependent and calmodulin dependent protein kinase, and the extent of phosphorylation by two kinases was additive. The 48K dalton band showed immunological reaction with monoclonal antibodies raised against human umbilical artery F actin, and it also comigrated with arterial smooth muscle actin on SDS gel electrophoresis. Plasma membranes prepared from vascular smooth muscle microsomes after extraction with actomyosin extraction buffer consisting of 2 mmol X litre-1 TRIS-maleate, pH 6.8, 0.25 mol X litre-1 sucrose, 0.5 mmol X litre-1 ATP, 0.2 mmol X litre-1 CaCl2, 0.1 mmol X litre-1 phenylmethylsulphonylfluoride, and 1 mmol X litre-1 dithiothreitol yielded membranes that were substantially free from cytoskeletal protein contamination. These membranes were enriched 60-80 fold in plasma membrane marker enzymes and showed energy dependent calcium uptake. In the extracted plasma membranes none of the proteins was phosphorylated by cAMP dependent or calmodulin dependent protein kinase. Thus these results show that protein phosphorylated in the unextracted microsomal fraction or unextracted plasma membranes are not integral plasma membrane proteins but represent tightly associated cytoskeletal proteins.
Cardiovasc Res 1986 Apr
PMID:Phosphorylation of cytoskeletal proteins tightly associated with the vascular smooth muscle membranes. 371 12

Several aspects of the mode of action of direct vasodilators are discussed. Nitro-compounds probably act via an intracellular formation of S-nitrosothiols, which stimulate cellular guanylate cyclase. Doubts, however, arise with regard to a generalization of this concept, e.g., methylene blue, an inhibitor of guanylate cyclase, interferes potently with the vasorelaxant action of nitroglycerin, but not with that of nitroprusside and sodium nitrite in KCl-stimulated rabbit aorta. Nitro-compounds do not interfere with transmembrane calcium movements. Hyperpolarization of the vascular smooth-muscle membrane, although reported to occur with nitroprusside, does not seem to be a common feature of the nitro-compounds. On the other hand, all nitro-compounds tested interfered with the noradrenaline-induced increase in 36-Cl steady-state exchange in rabbit aorta, and this effect could be mimicked by 8-Br-cGMP. Chemically skinned vascular smooth muscle was relaxed by pure cGMP-dependent protein kinase, but this effect requires confirmation. The action of hydralazine is augmented in chemically sympathectomized arteries and blocked by purines, such as adenosine, pointing to modulating role of purine-like compounds released from sympathetic nerve endings. The direct vasodilator action of hydralazine consists of a predominantly inhibitory effect on pharmacomechanical coupling. Membrane hyperpolarization with hydralazine has been reported. In addition to having direct effects on vascular smooth muscle, hydralazine can interfere with transmitter release by a prejunctional mechanism, and part of its vasorelaxant action seems to depend on the integrity of the endothelium in vascular smooth muscle.
J Cardiovasc Pharmacol 1984
PMID:Direct vasodilators with unknown modes of action: the nitro-compounds and hydralazine. 608 7

Effects of myocardial ischaemia on sarcoplasmic reticulum (SR) of dog hearts were investigated. Regional ischaemia was produced by occlusion of the left circumflex artery, and a microsomal fraction enriched in vesicles of SR was isolated from subendocardium (Endo) and subepicardium (Epi) of control and ischaemic areas of the heart. No significant changes occurred in ischaemic Epi. A loss of in vitro activities (ie calcium transport and ATPase) was found for SR from ischaemic Endo which paralleled the changes in the histology of the tissue. At 5 min of coronary occlusion, Ca2+ binding and Ca2+-ATPase activities of SR from ischaemic Endo were normal. A decrease in the activities of SR was first evident at 15 min after the occlusion, decreased further at about 30 min and remained at that level at 60 min of ischaemia. The maximal rate of Ca2+ uptake did not parallel the Ca2+-binding and Ca2+-ATPase activities. The degree of cAMP-dependent phosphorylation by endogenous and exogenous protein kinase was not different between SR from control and ischaemic areas. A participatory role of SR in the ischaemic impairment of left ventricular systolic and diastolic performance is discussed.
Cardiovasc Res 1983 Nov
PMID:Ischaemia-induced changes in canine cardiac sarcoplasmic reticulum. 622 97

HA1004, an isoquinolinesulfonamide and a cyclic nucleotide-dependent protein kinase inhibitor, is an intracellular calcium antagonist that produces vascular smooth muscle (VSM) relaxation in vitro. We studied the hemodynamic effects of intravenous (i.v.) infusions of HA1004 (0.1-2.0 mg/kg) in vivo in 8 newborn lambs, at rest and during pulmonary hypertension induced either by the i.v. infusion of U46619, a thromboxane A2 (TXA2) mimic, or by alveolar hypoxia. For comparison, we also studied the hemodynamic effects of i.v. infusions of nifedipine (15 and 40 micrograms/kg/min), a calcium entry blocker. At rest, HA1004 produced slight but significant changes in pulmonary and systemic arterial pressure (PAP, SAP) and pulmonary and systemic vascular resistances (PVR, SVR) (p < 0.05). During pulmonary hypertension induced by U46619, HA1004 decreased PAP 12-23% and PVR 9-33% (p < 0.05), whereas SAP decreased 7% and SVR decreased 14% at only one dose (p < 0.05). During pulmonary hypertension induced by alveolar hypoxia, HA1004 decreased PAP 6-32% and PVR 11-30% (p < 0.05), whereas SAP decreased 15% only at the highest dose (p < 0.05). Linear regression analysis of the pooled data demonstrated that HA1004 caused selective pulmonary vasodilation during pulmonary hypertension. Nifedipine decreased PAP 6 and 14% and SAP 5 and 17% during pulmonary hypertension. In newborn lambs with pulmonary hypertension, HA1004, an intracellular calcium antagonist, is more selective and potent than nifedipine, a calcium entry blocker, in decreasing PAP and therefore may be useful in treatment of children with pulmonary hypertension.
J Cardiovasc Pharmacol 1994 May
PMID:HA1004, an intracellular calcium antagonist, selectively attenuates pulmonary hypertension in newborn lambs. 752 65

Recent electrophysiologic studies have provided evidence suggesting that as many as six different Cl- conductances can be identified in the sarcolemma of cardiac myocytes isolated from various animal species and areas of the heart. These include Cl- conductances activated by stimulation of protein kinase A, protein kinase C, extracellular ATP, intracellular Ca2+, membrane stretch, and a basally active Cl- conductance. Many basic biophysical and pharmacological properties of these channels are presently unknown, and the only molecular information presently available suggests that the cAMP-activated Cl- conductance is due to cardiac expression of an isoform of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel normally found in epithelial cells. We used the polymerase chain reaction (PCR) to amplify four distinct regions corresponding to the cardiac CFTR gene product from several cardiac tissues to determine if the molecular distribution of CFTR matches the distribution of cAMP-dependent Cl- channels in native myocytes. Amplification of regions corresponding to the first nucleotide binding domain (NBD1), transmembrane segments (TS) VII-XII, and the regulatory (R) domain showed a precise correlation to tissues that electrophysiologically exhibit sarcolemmal cAMP-dependent Cl- channels, whereas region TS I-VI exhibited a distribution independent of the presence of cAMP-dependent Cl- channels.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Electrophysiol 1995 Apr
PMID:A plethora of cardiac chloride conductances: molecular diversity or a related gene family. 754 94

Rap1B, a ras-like protein expressed in high concentrations in human platelets, serves as a substrate for protein kinase A (PKA) and, eventually, protein kinase G (PKG). We measured rap1B phosphorylation by autoradiography of 32P-labeled proteins in platelets prelabeled with [32P]-orthophosphate. Platelets coincubated with histamine-stimulated human umbilical vein endothelial cells (EC) showed increased phosphorylation of the 50-Kd vasodilator-stimulated phosphoprotein (VASP) of 2.6 +/- 0.5-fold maximally and of rap1B of 17.5 +/- 7.1-fold maximally (mean +/- SE, n = 4). Incubation of platelets with prostacyclin (PGI2), the PGI2-analogue iloprost (ILO), the nitric oxide (NO) donors SIN-1 or sodium nitroprusside (SNP) showed greater concentration-dependent phosphorylation of rap1B than of VASP. Phosphorylation of rap1B had a slow time course and was irreversible in contrast to that of VASP, which was rapid and reversible. Phosphorylation of rap1B was dependent on an increase of platelet cyclic AMP and/or cyclic GMP. Very small concentrations of ILO (50 pM), PGI2 (1 nM), and SIN-1 (100 nM) increased rap1B phosphorylation. Rap1B phosphorylation could also be detected by Western blot after incubation of platelet-rich plasma (PRP) with ILO or SIN-1. Measurement of platelet rap1B phosphorylation is a novel tool that allows monitoring of the action of labile (PGI2, NO) and more stable (ILO, SIN-1, SNP) platelet inhibitors and vasodilators that increase intracellular cyclic AMP and cyclic GMP. Determination of rap1B phosphorylation by Western blot opens new possibilities of measuring platelet-EC interactions in clinical studies and of monitoring the action of systemically applied PGI2 analogues and nitrovasodilators in pharmacologic studies.
J Cardiovasc Pharmacol 1995 Apr
PMID:Platelet rap1B phosphorylation is a sensitive marker for the action of cyclic AMP- and cyclic GMP-increasing platelet inhibitors and vasodilators. 759 21


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