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)

L-type Ca(2+) channels are predominantly regulated by beta-adrenergic stimulation, enhancing L-type Ca(2+) current by increasing the mean channel open time and/or the opening probability of functional Ca(2+) channels. Stimulation of beta-adrenergic receptors (ARs) results in an increased cyclic adenosine monophosphate (cAMP) production by adenylate cyclase (AC) and consequently activation of protein kinase (PK) A and phosphorylation of L-type Ca(2+) channels by this enzyme. Beta(1)-Adrenergic receptors couple exclusively to the G protein Gs, producing a widespread increase in cAMP levels in the cell, whereas beta(2)-adrenergic receptors couple to both Gs and Gi, producing a more localized activation of L-type Ca(2+) channels. Other signaling intermediates (protein kinase C, protein kinase G or protein tyrosine kinase (PTK)) either have negative effects on L-type Ca(2+) current, or they interact with the stimulatory effect of the protein kinase A pathway.
Cardiovasc Res 2005 Jan 01
PMID:Molecular aspects of adrenergic modulation of cardiac L-type Ca2+ channels. 1562 Oct 31

We investigated the effects of the vasoconstrictor endothelin-1 (ET-1) on the whole-cell ATP-sensitive K+ (KATP) currents of smooth muscle cells that were isolated enzymatically from rabbit coronary artery (CASMCs) and pulmonary artery (PASMCs). The size of the KATP current did not differ significantly between CASMCs and PASMCs. ET-1 reduced the KATP current in a concentration-dependent manner, and this inhibition was greater in PASMCs than in CASMCs (half-inhibition values of 12.20 nM and 1.98 nM in CASMCs and PASMCs, respectively). However, the level of inhibition induced by other vasoconstrictors (angiotensin II, norepinephrine, and serotonin) were not significantly different between CASMCs and PASMCs. Pretreatment with the protein kinase C (PKC) inhibitors staurosporine (100 nM) and GF 109203X (1 microM) prevented ET-1-induced inhibition of the KATP current in both arterial smooth muscle cell preparations. The PKC activators phorbol-12,13-dibutyrate (PDBu) and 1-olelyl-2-acetyl-sn-glycerol (OAG) reduced the KATP current in dose-dependent manner. Although the numbers of ET receptors were not significantly different between the 2 arterial smooth muscle cell preparations, the effects of PDBu and OAG were greater on PASMCs. ET-1-induced inhibition of the KATP current was unaffected by the PKA inhibitor Rp-cAMPs (100 microM) and PKA inhibitory peptide (5 microM).
J Cardiovasc Pharmacol 2005 Feb
PMID:Endothelin-1 acts via protein kinase C to block KATP channels in rabbit coronary and pulmonary arterial smooth muscle cells. 1565 57

We examined the effects of the protein kinase C (PKC) inhibitor staurosporine (ST) on voltage-dependent K (KV) channels in rabbit coronary arterial smooth muscle cells. ST inhibited the KV current in a dose-dependent manner with a Kd value of 1.3 microM. The inhibition of the KV current by ST was voltage-dependent between -30 and +10 mV. The additive inhibition of the KV current by ST was voltage-dependent throughout the activation voltage range. The rate constants of association and dissociation of ST were 0.63 microM s and 0.92 s, respectively. ST produced use-dependent inhibition of the KV current. ST shifted the activation curve to more positive potentials but did not have any significant effect on the voltage dependence of the inactivation curve. ST did not have any significant effects on other types of K channel. Another PKC inhibitor, chelerythrine, and PKA inhibitor peptide (PKA-IP) had little effect on the KV current. These results suggest that ST interacts with KV channels that are in the closed state and that ST inhibits KV channels in the open state in a manner that is phosphorylation-independent and voltage-, time-, and use-dependent.
J Cardiovasc Pharmacol 2005 Mar
PMID:Staurosporine inhibits voltage-dependent K+ current through a PKC-independent mechanism in isolated coronary arterial smooth muscle cells. 1572 52

Cardiac troponin I (cTnI) is a key regulatory protein in cardiac muscle contraction and relaxation, linking Ca(2+)-troponin C binding with activation of crossbridge reactions with the thin filament. In recent years, it has become increasingly apparent that myofilament properties as well as changes in intracellular Ca(2+) have a major role in the dynamic modulation of contractile function. The phosphorylation of specific serine and threonine residues on cTnI by several different kinases represents a major physiological mechanism for alteration of myofilament properties. Furthermore, altered thin filament function plays an important role in the contractile dysfunction associated with heart failure. Modification of cTnI by protein kinases A and C has been extensively studied with especially useful information deriving from (a) in vitro studies in reconstituted detergent-skinned fibre bundles in which endogenous cTnI was replaced with various targeted cTnI mutants and (b) transgenic animals in which endogenous cTnI was similarly manipulated through overexpression of cardiomyocyte-targeted cTnI mutants. cTnI may also be specifically modified by protein kinase G, p21-activated kinases and by dephosphorylation. This review focuses on recent advances in understanding the mechanisms of cTnI modification by these kinases and the consequent functional effects both under physiological conditions and in pathophysiological settings.
Cardiovasc Res 2005 Apr 01
PMID:Regulation of cardiac contractile function by troponin I phosphorylation. 1576 44

Myocardial ischemia is associated with increased production of cyclic adenosine monophosphate (cAMP), with potentially deleterious effects. We hypothesized that the ischemia-induced activation of cAMP-dependent protein kinase A (PKA), could beneficially be inhibited by a PKA-inhibitor N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinoline-sulfonamide (H-89). H-89 when given to isolated perfused rat hearts before 30 minutes of global ischemia-reperfusion improved postischemic function and decreased infarct size. In another series, H-89 administered prior to preconditioning by 10 minutes of transient global ischemia decreased PKA activity (measured at the end of the preconditioning protocol) and augmented postischemic mechanical recovery. H-89 given for 5 minutes before the 10 minutes of transient ischemia further decreased infarct size from 13.4 +/- 1.0% (preconditioning alone) to 7.0 +/- 0.93 (P < 0.01). In a third series, forskolin (0.3 muM, 5 minutes, 10 minutes washout prior to ischemia) increased PKA activity and reduced infarct size. Prior H-89 decreased PKA activity after 5 minutes of forskolin and further reduced infarct size versus forskolin alone. In conclusion, three procedures increased postischemic recovery and reduced infarct size: H-89; preconditioning by transient ischemia; or forskolin as a preconditioning-mimetic. PKA-inhibition by H-89 further decreased infarct size beyond preconditioning or forskolin. Despite the reservation that H-89 could be non-selective in its actions, we propose H-89 as a candidate cardioprotective agent.
J Cardiovasc Pharmacol 2005 Apr
PMID:H-89, a non-specific inhibitor of protein kinase A, promotes post-ischemic cardiac contractile recovery and reduces infarct size. 1577 23

We have previously shown that type I cGMP-dependent protein kinase (PKG) can alter the phenotype of cultured vascular smooth muscle cells (VSMCs). Although the expression of contractile proteins in VSMCs has been shown to be modulated with the induction of PKG, experiments in which PKG inhibition brings about reduced expression of contractile markers have not been performed. To more thoroughly examine the role of PKG in the expression of contractile proteins, recombinant adenovirus containing the PKG coding sequence (AD-PKG) was used to induce gene expression and morphologic changes in adult rat aortic VSMCs. Cells expressing PKG, but not control adenovirus-infected cells, began to express a specific marker protein for the contractile phenotype, smooth muscle myosin heavy chain (SMMHC), within 48 hours of PKG induction. The morphology of the AD-PKG-infected cells began to change from a fibroblastic phenotype to a spindle-shaped phenotype within 72 hours after PKG induction. The specific cell-permeable PKG inhibitory peptide DT-2, but not control peptides, reversed the biochemical and morphologic changes associated with PKG expression. These results suggest that PKG expression and activity in cultured VSMCs is capable of altering the VSMC phenotype. These data also verify the intracellular action of DT-2 and reveal uptake and dynamic properties of this PKG-inhibiting peptide.
J Cardiovasc Pharmacol 2005 May
PMID:Inhibition of cGMP-dependent protein kinase reverses phenotypic modulation of vascular smooth muscle cells. 1582 35

Leptin resistance leads to obesity and may affect responses to the second messenger cGMP. We tested the hypothesis that the myocardial negative metabolic response to cGMP would be enhanced in leptin-resistant animals. This hypothesis was tested in anesthetized open-chest Zucker obese (n = 16) and age-matched control rats (n = 13). Coronary blood flow (microspheres) and O2 extraction (microspectrophotometry) measurements were used to determine myocardial O2 consumption (VO2). Protein phosphorylation by cGMP protein kinase and cAMP phosphodiesterase activity were also determined. Either vehicle (saline) or 8-Br-cGMP (10(-3) M) was topically applied to the left ventricular surface. Body weight was significantly greater in the obese rats (523 +/- 17 versus 322 +/- 12 g). There were no hemodynamic differences between groups. There was no difference in VO2 between lean (52 +/- 13 mL O2/min/100 g) and obese (54 +/- 9) vehicle-treated rats. 8-Br-cGMP significantly lowered VO2 in obese (35 +/- 6) but not lean (45 +/- 7) rats. This was not related to altered protein phosphorylation by the cGMP protein kinase. Cyclic GMP inhibited cAMP phosphodiesterase activity in lean but not obese hearts. Thus, the high myocardial oxygen consumption of lean rats was not significantly affected by cGMP but was reduced in obese hearts. This appeared to be related to a reduced inhibition of cAMP phosphodiesterase activity by cGMP in the Zucker obese rat.
J Cardiovasc Pharmacol 2005 Jun
PMID:Negative metabolic effects of cGMP are enhanced in obese rat hearts. 1589 79

Cardiac excitation-contraction coupling occurs by a calcium ion-mediated mechanism in which the signal of action potential is converted into Ca2+ influx into the cardiomyocytes through the sarcolemmal L-type calcium channels. This is followed by Ca2+-induced release of additional Ca2+ ions from the lumen of the sarcoplasmic reticulum into the cytosol via type 2 ryanodine receptors (RyR2). RyR2 channels form large complexes with additional regulatory proteins, including FKBP12.6 and calsequestrin 2 (CASQ2). Catecholamines, released into the body fluids during emotional or physical stress, activate Ca2+-induced Ca2+ release by protein kinase A-mediated phosphorylation of RyR2. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an insidious, early-onset and highly malignant, inherited disorder characterized by effort-induced ventricular arrhythmias in the absence of structural alterations of the heart. At least some cases of sudden, unexplained death in young individuals may be ascribed to CPVT. Mutations of the RyR2 gene cause autosomal dominant CPVT, while mutations of the CASQ2 gene may cause an autosomal recessive or dominant form of CPVT. The steps of the molecular pathogenesis of CPVT are not entirely clear, but inappropriate "leakiness" of RyR2 channels is thought to play a role; the underlying mechanisms may involve an increase in the basal activity of the RyR2 channel, alterations in its phosphorylation status, a defective interaction of RyR2 with other molecules or ions, such as FKBP12.6, CASQ2, or Mg2+, or its abnormal activation by extra- or intraluminal Ca2+ ions. Beta-adrenergic antagonists have proven to be of value in prevention of arrhythmias in CPVT patients, but occasional treatment failures call for alternative measures. There is great interest at present for the development of novel antiarrhythmic drugs for CPVT, as the same approaches may be applied for treatment of more common forms of life-threatening arrhythmias, such as those arising during ischemia and heart failure.
Cardiovasc Res 2005 Aug 15
PMID:Catecholaminergic polymorphic ventricular tachycardia: recent mechanistic insights. 1591 75

During cardiac filling, the relative contribution of distension of interstitial collagen, of distension of cytoskeletal proteins, and of low-grade diastolic cross-bridge cycling in the generation of diastolic left ventricular (LV) pressure remains unclear. In failing myocardium, interstitial collagen deposition and cross-linking are augmented. This increase in collagen deposition is accompanied by expression of a stiffer isoform of titin in the cardiomyocytes. Higher diastolic stiffness of failing myocardium is therefore not necessarily related to increased interstitial collagen content. Moreover, phosporylation of titin by protein kinase A and G, and inhibition of titin-actin interaction by cytosolic calcium allow for dynamic modulation of its diastolic tension generation and could account for acute shifts of myocardial distensibility. Acute shifts of myocardial distensibility, as occur in hypertrophy or in demand ischemia, have usually been attributed to a diastolic resurgence of cross-bridge interaction. In hypertrophied and failing myocardium, the recent demonstrations of diastolic calcium release from the ryanodine receptor, of deficient diastolic calcium removal from the cytosol, and of enhanced myofilamentary calcium sensitivity support residual diastolic cross-bridge interaction. In demand ischemia, the role of calcium overload in the reduction of diastolic LV distensibility is less clear because of correction of the reduced diastolic LV distensibility by quick stretches but not by a calcium desensitizer. Simultaneous imposition in animal models of multiple molecular changes involving interstitial, cytoskeletal, and myofilamentary proteins could elucidate their relative importance for myocardial stiffness and lead to selective correction of diastolic LV dysfunction as a novel mode of heart-failure therapy.
Prog Cardiovasc Dis
PMID:Matrix, cytoskeleton, or myofilaments: which one to blame for diastolic left ventricular dysfunction? 1599 Nov 55

Cardiomyocyte survival and growth are regulated by the action of extracellular ligands that activate intracellular signaling cascades. The Raf family of protein serine/threonine kinases plays a critical role in the regulation of cardiomyocyte survival and growth. The three Raf family members, Raf-1, B-Raf, and A-Raf, are highly homologous, and they are all expressed in the heart. Protein kinases of the Raf family phosphorylate and activate the mitogen-activated protein kinase kinases (MKKs, also known as MEKs). MKKs, in turn, are dual-specificity threonine and tyrosine kinases that phosphorylate and activate extracellular signal-regulated kinases (ERKs). ERKs phosphorylate a variety of substrates, including nuclear transcription factors, which regulate cell physiology. Raf proteins also have antiapoptotic activity that is independent of MKK and ERK. In this review, the role of Raf family members in the regulation of cardiomyocyte survival and growth will be discussed.
Trends Cardiovasc Med 2005 Aug
PMID:Role of raf proteins in cardiac hypertrophy and cardiomyocyte survival. 1618 33


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