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PubMed1996

Successful radiofrequency ablation of accessory pathways with the first energy delivery: the anatomic and electrical characteristics.

Successful ablation of accessory pathways has been achieved at the first energy delivery site in some patients, but factors permitting success at the first site are unclear. Accessory pathway location, surface and endocardial electrogram characteristics in each location were analysed and compared between the patients with first site block (group A, 34 patients) and those in whom multiple sites (median seven sites) were required (group B, 133 patients). No patients with right free-wall pathways had first site block. In group A surface electrocardiograms were more pre-excited (QRS duration: 132 +/- 20 vs 120 +/- 17 ms, P < 0.01). For left free-wall and septal pathways, the interval from the onset of the earliest delta wave on surface electrocardiogram to local ventricular activation (QRS-V) was more negative and the local atrioventricular interval (AV) was shorter in group A; the positive predictive value of a QRS-V < or = 0 ms, an AV < or = 30 ms and the presence of a possible accessory pathway potential was 67% for left free-wall and of a QRS-V < or = -10 ms with an AV < or = 30 ms was 100% for septal pathways. During retrograde mapping of concealed left free-wall and right anteroseptal pathways (first site block was not achieved in other locations) the positive predictive value of a local ventriculoatrial interval < or = 30 ms was 55%. Accessory pathway location correlated strongly with the chances of first site block, suggesting that anatomical features are important. Maximizing pre-excitation may be of benefit in achieving first site block. Delivery of energy to a site with special endocardial electrogram features was associated with an increased likelihood of first site block.

Accessory Nerve↗
PubMed1989

Closed-chest ablation of left lateral atrioventricular accessory pathways.

Thirty patients with a left lateral accessory pathway and drug refractory tachycardia underwent attempted transcatheter ablation of the accessory pathway. Three had a concealed accessory pathway and 27 had the Wolff-Parkinson-White syndrome. A quadripolar electrode catheter was positioned within the coronary sinus in order to locate the earliest retrograde atrial activation during orthodromic reciprocating tachycardia. The appropriate bipole was used as the radiographic and electrophysiologic reference of the insertion of the accessory pathway. A catheter was then introduced into the left atrium, through a patent foramen ovale (six patients) or after transseptal catheterization (14 patients) according to Croft's technique, or using a retrograde transaortic approach (10 patients). The mitral annulus was mapped with the left atrial catheter in order to record a synchronous or earlier atrial deflection than reference during reciprocating tachycardia. VA' time at the preablation site was 82 +/- 12 ms. Two to seven 160 J cathodal shocks (650 +/- 205 J cumulative per patient) were delivered at this site in 38 sessions. No significant side-effects occurred except for one case of right coronary artery spasm leading to inferior wall infarction. Following fulguration, accessory pathway conduction was abolished in all patients but one with a second accessory pathway. During follow-up of 1-34 months, all patients but one were free of tachycardia: reciprocating tachycardia recurred in one patient, who had a concealed accessory pathway, on the third day. Accessory pathway conduction, assessed in 10 other patients 3-26 months after the procedure, was absent. Coronary arteriography performed in seven patients was normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Electrocardiographic patterns during Holter monitoring in patients with first and second degree A-V block due to 'dual A-V nodal pathways'.

The electrocardiographic patterns, observed during 24-h Holter monitoring, of 10 patients (mean age 35 +/- 22 years) with first and second degree A-V block due to dual A-V nodal pathways are reported. Recordings were selected according to the presence of: sudden and persistent prolongation of the PR interval: sudden normalization of the PR interval: 'atypical' Wenckebach sequences showing sudden and pronounced prolongation of any PR interval prior to the blocked P wave. Besides the already recognized pattern, new aspects were identified: (1) Wenckebach sequences in the slow and fast pathways characterized by a progressive increase in the PR interval until a blocked P wave occurred during long and short PR interval periods, respectively; (2) Wenckebach periods first in the slow and then in the fast pathway; (3) 2:1 A-V block with a normal PR interval in the conducted beat after a Wenckebach sequence in the slow pathway; (4) Wenckebach in the fast pathway and, subsequently, in the slow one characterized by a slight prolongation of the PR interval for some beats followed by a sudden and pronounced increase in the PR interval of one beat and a subsequent progressive slight PR prolongation until a blocked P wave occurred; (5) Wenckebach sequence in the fast pathway with subsequent conduction over the slow pathway without a blocked P wave; (6) blocked P waves during both long and short PR interval periods with slight prolongation of the preceding PR interval. The electrophysiological mechanisms involved in these electrocardiographic patterns together with the nature (anatomical or functional) of the intranodal pathways and the clinical significance of this type of block are discussed.

Adolescent↗
PubMed1994

Radiofrequency ablation of accessory pathways: implications of accumulated experience and time dedicated to procedures.

Previous reports on radiofrequency ablation of accessory pathways have shown that the experience of the operator is of crucial importance in reducing fluoroscopy time and achieving higher success rates. However, a detailed analysis of this important issue has not been previously attempted. We analysed 71 consecutive ablation procedures undertaken at St George's Hospital by the same electrophysiology group and always with the same first operator. Of all procedures, 66 (91.6%) were successful, as judged by abolition of accessory pathway conduction without recurrence within the next 24 h. Failures included two out of 38 left-sided pathway procedures (5.3%), one out of 11 intermediate septal (9.1%) and four out of 22 right-sided pathway procedures (18.2%). These differences were not statistically significant. Average procedure and screening times for all procedures were 162.9 +/- 86.0 min and 56.8 +/- 48.2 min respectively, whereas the median of the number of discharges was 12, ranging from one to 51. There was no significant difference between pathway groups or between concealed and non-concealed pathways in respect to procedure and screening time or number of discharges. There was a significant tendency towards decreased procedure and screening times with accumulating experience and this was similar for all pathway groups. There was also a tendency towards improved cumulative success rates with time dedicated to procedures. We conclude that a certain amount of ablation experience is required, even by experienced electrophysiologists, before a relatively high success rate without long radiation exposure can be achieved, regardless of the location or the mode of conduction of the pathway.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

The Wolff-Parkinson-White syndrome: the cellular substrate for conduction in the accessory atrioventricular pathway.

The longstanding quest for the anatomical basis of the Wolff-Parkinson-White syndrome has left many unanswered questions. The ultrastructural morphology of the myocytes comprising accessory atrioventricular pathways, which are capable of rapid and variable conduction, is central to understanding the development and behaviour of this congenital anomaly, but remains unknown. Examination of three surgically resected pathways was performed to determine their underlying cellular morphology and the pattern of intercellular coupling, by correlative light microscopy, electron microscopy and confocal scanning laser microscopy combined with immunohistochemical localization of the cardiac gap-junctional protein, connexin43. Two left-sided pathways were composed of myocardium of 'normal working ventricular' type. The right-sided pathway was composed almost entirely of highly abnormal myocytes characterized by aberrant myofibril organisation, with a lack of A-band material and abnormal mitochondria, but normal intact intercalated disks no different from those seen in left-sided pathways. The gap junctions of all pathways were composed of connexin43 distributed as in ventricular myocardium, and not as found in atrial or atrioventricular nodal tissues. While myocytes of abnormal structure were present in one of the accessory atrioventricular pathways examined, all pathways had morphologically normal gap junctions, the structures responsible for efficient intercellular coupling, with a pattern of distribution suggestive of working ventricular myocardium.

Adolescent↗
PubMed1995

Successful radiofrequency catheter ablation of right sided accessory pathways during sustained atrial fibrillation.

Up to now there have been no descriptions in the literature of endocardial catheter mapping and successful radiofrequency catheter ablation of the right sided accessory pathway during sustained atrial fibrillation. We attempted ablation of a right posterolateral and a right lateral accessory pathway during sustained atrial fibrillation with rapid anterograde conduction over the accessory pathway in two patients with Wolff-Parkinson-White syndrome. In both patients (aged 47 and 52 years), sustained atrial fibrillation occurred during the electrophysiological study to assess accessory pathway conduction properties. The mean ventricular rate during atrial fibrillation was 180 and 170 beats.min-1, respectively. Both patients were successfully ablated with a single radiofrequency impulse. At the successful ablation sites, a potential of the accessory pathway was consistently recorded preceding the onset of preexcitation in the surface electrogram, by 25 ms in patient 1 and 30 ms in patient 2. The unipolar electrogram recorded from the ablation catheter showed a QS morphology and the accessory pathway potential preceded the intrinsic deflection by 10 ms in both patients. Onset of the ventricular electrogram (patient 1: -20 ms; patient 2: -15 ms) and its activation time (patient 1: -15 ms; patient 2: +5 ms) in relation to the onset of preexcitation in the surface electrocardiogram also indicated the close proximity of the ablation catheter to the accessory pathway. Preexcitation disappeared within 2 s after energy application in both patients. Thus, radiofrequency catheter ablation of right sided accessory pathways during sustained atrial fibrillation is feasible and may obviate the need for medical or electrical cardioversion.(ABSTRACT TRUNCATED AT 250 WORDS)

Atrial Fibrillation↗
PubMed1986

Noninvasive support for and characterization of multiple intranodal pathways in patients with mitral valve disease and atrial fibrillation.

Twenty-four-hour ambulatory ECG recordings were made in 22 patients with mitral valve disease and sustained atrial fibrillation. Computer analysis was used to stratify 64-beat periods according to the average ventricular rate levels. The distribution of pooled RR-intervals from heart-rate levels 50-60, 60-70 ... 160-170 were then presented as histograms, using a 20 ms width. This heart-rate stratified analysis revealed a bi- or trimodal RR-distribution in 16 of the 22 patients. This finding was interpreted as indicating the presence of two separate atrionodal pathways and in some cases nodal escape activity in addition. A limited heart-rate range may have obscured this phenomenon in 5 of the 6 cases without signs of bimodality. At high heart rates, AV-nodal conduction occurred via a 'fast pathway' whilst at successively lower heart rates, this conduction was blocked and a 'slower pathway' was used instead. In addition, at successively slower rates, the dominant cycle of conduction via either pathway tended to lengthen according to a linear relationship. The change of dominance from the fast to the slow pathway occurred between 90 and 120 beats per minute in almost all cases. The further electrophysiological characterization of patients with 2 pathways was done by calculation of differences and ratios between lengths of dominant cycles of different pathways at the rate of change of dominance. The findings may serve as reference data for further studies of AV-nodal conduction using the same method. Furthermore, the study strongly indicates that dual AV-nodal pathways are an ubiquitous phenomenon and supports the hypothesis that even in man, AV-nodal input follows two main routes: along the crista terminals between the coronary sinus and the tricuspid valve and from the interatrial septum.

Aged↗
PubMed2001

Mixed lineage kinase LZK forms a functional signaling complex with JIP-1, a scaffold protein of the c-Jun NH(2)-terminal kinase pathway.

Leucine zipper-bearing kinase (LZK) is a novel member of the mixed lineage kinase (MLK) protein family, the cDNA of which was first cloned from a human brain cDNA library [Sakuma, H., Ikeda, A., Oka, S., Kozutsumi, Y., Zanetta, J.-P., and Kawasaki, T. (1997) J. Biol. Chem. 272, 28622-28629]. Several MLK family proteins have been proposed to function as MAP kinase kinase kinases in the c-Jun NH(2) terminal kinase (JNK)/stress-activated protein kinase (SAPK) pathway. In the present study, we demonstrated that, like other MLKs, LZK activated the JNK/SAPK pathway but not the ERK pathway. LZK directly phosphorylated and activated MKK7, one of the two MAPKKs in the JNK/SAPK pathway, to a comparable extent to a constitutive active form of MEKK1 (MEKK1DeltaN), suggesting a biological role of LZK as a MAPKKK in the JNK/SAPK pathway. Recent studies have revealed the essential roles of scaffold proteins in intracellular signaling pathways including MAP kinase pathways. JIP-1, one of the scaffold proteins, has been shown to be associated with MLKs, MKK7, and JNK [Whitmarsh, A.J., Cavanagh, J., Tournier, C., Yasuda, J., and Davis, R.J. (1998) Science 281, 1671-1674], suggesting the presence of a selective signaling pathway including LZK, MKK7, and JNK. Consistent with this hypothesis, we provided evidence that LZK is associated with the C-terminal region of JIP-1 through its kinase catalytic domain. In addition, LZK-induced JNK activation was markedly enhanced when LZK and JNK were co-expressed with JIP-1. These results constituted important clues for understanding the molecular mechanisms regulating the signaling specificities of various JNK activators under different cellular conditions.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Patterns of evolutionary rate variation among genes of the anthocyanin biosynthetic pathway.

The anthocyanin biosynthetic pathway is responsible for the production of anthocyanin pigments in plant tissues and shares a number of enzymes with other biochemical pathways. The six core structural genes of this pathway have been cloned and characterized in two taxonomically diverse plant species (maize and snapdragon). We have recently cloned these genes for a third species, the common morning glory, Ipomoea purpurea. This additional information provides an opportunity to examine patterns of evolution among genes within a single biochemical pathway. We report here that upstream genes in the anthocyanin pathway have evolved substantially more slowly than downstream genes and suggest that this difference in evolutionary rates may be explained by upstream genes being more constrained because they participate in several different biochemical pathways. In addition, regulatory genes associated with the anthocyanin pathway tend to evolve more rapidly than the structural genes they regulate, suggesting that adaptive evolution of flower color may be mediated more by regulatory than by structural genes. Finally, for individual anthocyanin genes, we found an absence of rate heterogeneity among three major angiosperm lineages. This rate constancy contrasts with an accelerated rate of evolution of three CHS-like genes in the Ipomoea lineage, indicating that these three genes have diverged without coordinated adjustment by other pathway genes.

Acyltransferases↗
PubMed1998

Differential involvement of indole-3-acetic acid biosynthetic pathways in pathogenicity and epiphytic fitness of Erwinia herbicola pv. gypsophilae.

Erwinia herbicola pv. gypsophilae (Ehg), which induces galls on Gypsophila paniculata, harbors two major pathways for indole-3-acetic acid (IAA) synthesis, the indole-3-acetamide (IAM) and indole-3-pyruvate (IPyA) routes, as well as cytokinin biosynthetic genes. Mutants were generated in which the various biosynthetic routes were disrupted separately or jointly in order to assess the contribution of IAA of various origins and cytokinins to pathogenicity and epiphytic fitness. Inactivation of the IAM pathway or cytokinin biosynthesis caused the largest reduction in gall size. Inactivation of the IPyA pathway caused a minor, nonsignificant decrease in pathogenicity. No further reduction in gall size was observed by the simultaneous inactivation of both IAA pathways only or in combination with that of cytokinin production. However, inactivation of the IPyA pathway caused a 14-fold reduction in the population of Ehg on bean plants. Inactivation of the IAM pathway or cytokinin production did not affect epiphytic fitness. While the apparent transcriptional activity of iaaM-inaZ fusion increased slightly in cells of Ehg on bean and gypsophila leaves, compared with that in culture, very high levels of induction were observed in cells injected into gypsophila stems. In contrast, moderate levels of induction of ipdC-inaZ in Ehg were observed on leaves of these plants and in gypsophila stems, when compared with that in culture. These results suggest that the IAM pathway is involved primarily in gall formation and support the main contribution of the IpyA pathway to the epiphytic fitness of this bacterial species.

Base Sequence↗
PubMed2006

Thioredoxin-ASK1 complex levels regulate ROS-mediated p38 MAPK pathway activity in livers of aged and long-lived Snell dwarf mice.

We have proposed that the age-associated increase of reactive oxygen species (ROS) by electron transport chain (ETC) dysfunction may cause the elevated basal level of p38 MAPK stress response pathway activity. However, the mechanism by which ROS activates this pathway is not clear. Here we propose that activation of the p38 MAPK pathway by complex I (CI) generated ROS, in response to rotenone (ROT) treatment, is based on the ability of reduced Trx to bind to and inhibit ASK 1 and its release from the complex upon oxidation. This balance of free vs. bound ASK1 regulates the level of p38 MAPK pathway activity. To support this mechanism we demonstrate that the production of ROS by ROT treated AML12 hepatocyte cells dissociates the Trx-ASK1 complex, thereby increasing p38 MAPK pathway activity. This mechanism is supported by the ability of N-acetyl cysteine (NAC) to prevent dissociation of Trx-ASK1 and activation of the p38 MAPK pathway. We also demonstrated that the ratio of ASK1/Trx-ASK1 increases in aged mouse livers and that this correlates with the increased basal activity of the p38 MAPK pathway. The longevity of Snell dwarf mice has been attributed to their resistance to oxidative stress. A comparison of the levels of Trx-ASK1 in young and aged dwarfs showed a higher abundance of the complex than in their age-matched controls. These results, which are indicative of a decreased level of oxidative stress, suggest that increased ROS production in aged liver may alter the ratio of ASK1 and Trx-ASK1, thereby increasing the age-associated basal level of p38 MAPK pathway activity.

Aging↗
PubMed1995

Propofol has no direct effect on sinoatrial node function or on normal atrioventricular and accessory pathway conduction in Wolff-Parkinson-White syndrome during alfentanil/midazolam anesthesia.

BACKGROUND: Propofol has been implicated as causing intraoperative bradyarrhythmias. Furthermore, the effects of propofol on the electrophysiologic properties of the sinoatrial (SA) node and on normal atrioventricular (AV) and accessory pathways in patients with Wolff-Parkinson-White syndrome are unknown. Therefore, this study examined the effects of propofol on the cardiac electrophysiologic properties in humans to determine whether propofol promotes bradyarrhythmias and its suitability as an anesthetic agent in patients undergoing ablative procedures. METHODS: Twelve patients with Wolff-Parkinson-White syndrome undergoing radiofrequency catheter ablation were studied. Anesthesia was induced with alfentanil (50 micrograms/kg), midazolam (0.15 mg/kg), and vecuronium (20 mg) and maintained with alfentanil (2 micrograms.kg-1.min-1) and midazolam (1-2 mg, every 15 min, as needed). A electrophysiologic study was performed consisting of measurement of the effective refractory period of the right atrium, AV node, and accessory pathway and the shortest cycle length of the AV node and accessory pathway during antegrade stimulation plus the effective refractory period of the right ventricle and accessory pathway and the shortest cycle length of the accessory pathway during retrograde stimulation. Determinants of SA node function including sinus node recovery time, corrected sinus node recovery time, and SA conduction time; intraatrial conduction time and atrial-His interval also were measured. Reciprocating tachycardia was induced by rapid right atrial or ventricular pacing, and the cycle length and atrial-His, His-ventricular, and ventriculoatrial intervals were measured. Alfentanil/midazolam was then discontinued. Propofol was administered (bolus 2 mg/kg + 120 micrograms.kg-1.min-1), and the electrophysiologic measurements were repeated. RESULTS: Propofol caused a statistically significant but clinically unimportant prolongation of the right atrial refractory period. The effective refractory periods of the AV node, right ventricle, and accessory pathway, as well as the shortest cycle length, were not affected. Parameters of SA node function and intraatrial conduction also were not affected. Sustained reciprocating tachycardia was inducible in 8 of 12 patients, and propofol had no effect on its electrophysiologic properties. All accessory pathways were successfully identified and ablated. CONCLUSIONS: Propofol has no clinically significant effect on the electrophysiologic expression of the accessory pathway and the refractoriness of the normal AV conduction system. In addition, propofol has no direct effect on SA node activity or intraatrial conduction; therefore, it does not directly induce bradyarrhythmias. It is thus a suitable agent for use in patients undergoing ablative procedures who require either a neuroleptic or general anesthetic.

Adolescent↗
PubMed2001

High-throughput drug screening of the DPC4 tumor-suppressor pathway in human pancreatic cancer cells.

OBJECTIVE: To screen a library of small chemicals for compounds that activate the DPC4 signal transduction pathway in a human pancreatic cancer cell line. SUMMARY BACKGROUND DATA: Various tumor-suppressor genes are mutated in all human cancers. Specifically, DPC4 (deleted in pancreatic carcinoma, locus 4 or MADH4/SMAD4) is a tumor-suppressor gene mutated in approximately 50% of human pancreatic adenocarcinomas. DPC4 plays an important role in the well-studied transforming growth factor-beta (TGFbeta) signaling pathway. It would be useful to identify therapies that augment or restore the downstream functions of this critical signal transduction pathway, in hopes that such therapy would have a rational role in anticancer therapy. METHODS: Using a commercially available plasmid vector with a luciferase reporter gene already incorporated, a DPC4-specific reporter construct was genetically engineered. This was done by inserting six copies of the palindromic Smad binding element (6SBE), which is a DNA binding element specific for DPC4, in front of the minimal promoter in the plasmid. This construct was then stably integrated into the genome of a human pancreatic cancer cell line (PANC-1) that has wild-type DPC4. Several stably transfected clones were tested for basal luciferase expression and inducibility with TGFbeta, which is known to activate the DPC4 signal transduction pathway. A single transfected clone was chosen for the drug screen based on basal luciferase (reporter) expression and TGFbeta inducibility. A systematic screen of the chemical library was then performed, using luciferase activity to detect DPC4 activity and induction of the signaling pathway. RESULTS: A high-throughput system based on this stably integrated reporter system was used to screen a library of 16,320 random compounds to identify agents that conferred robust augmentation of the DPC4 signal transduction pathway. Of the 16,320 compounds screened, 11 were associated with a 2- to 5-fold induction of luciferase activity, and one with a 12-fold activation. The latter compound was shown to be a novel histone deacetylase inhibitor and was further characterized. CONCLUSIONS: These results confirm the feasibility of a specific high-throughput reporter system to screen a large compound library in human cells efficiently. The screening identified several compounds capable of augmenting DPC4-specific luciferase reporter activity, and a specific mechanism for one compound was identified. The discovery of such agents will aid our understanding of complex tumor-suppressive signaling pathways and may identify other potential therapeutic targets within this critical signaling pathway. In addition, random drug screening provides an unbiased method for identifying drugs or lead compounds for potential therapeutic use.

Adenocarcinoma↗
PubMed2002

Endothelium and disordered fibrin turnover in the injured lung: newly recognized pathways.

OBJECTIVES: To review derangements of pathways of fibrin turnover that promote pathologic fibrin deposition in the acute respiratory distress syndrome and to review the contribution of the endothelium and parenchymal lung cells to the derangements. In addition, to review how these pathways can be exploited in specific clinical circumstances, including sepsis and acute lung injury. Lastly, to review newly recognized posttranscriptional and urokinase-dependent pathways by which the fibrinolytic system is regulated in the lung. DATA SOURCES: Medical literature published in English from 1966 to present. DATA SUMMARY: Local abnormalities of fibrin turnover in the injured lung recapitulate the systemic changes observed in sepsis. In both circumstances, the procoagulant response is increased, whereas fibrinolytic activity is concurrently depressed. The increased procoagulant activity is related to tissue factor associated with factor VII/VIIa. Fibrinolytic activity in the vasculature is mainly attributable to tissue plasminogen activator, whereas extravascular fibrinolytic activity in the lung is mainly attributable to urokinase plasminogen activator (uPA). Depressed fibrinolytic activity is in large part attributable to plasminogen activator inhibitor-1. In sepsis, activated protein C is also deficient, potentiating the inflammatory response, coagulopathy, and depressed fibrinolysis. Recombinant human activated protein C (drotrecogin alfa [activated]) was successful as an intervention for sepsis in a recent phase 3 clinical trial (PROWESS). Recently, novel posttranscriptional pathways that regulate expression of uPA, its receptor (uPAR), and plasminogen activator inhibitor-1 have been identified. The responsible mechanisms involve cis-trans interactions between newly recognized messenger RNA (mRNA) binding sequences and mRNA binding proteins. A 51 nucleotide mRNA binding sequence within the coding region of uPAR mRNA interacts with a novel 50-kDa mRNA binding protein to destabilize the message. Sequences within the 3' untranslated region of uPA or plasminogen activator inhibitor-1 mRNA interact with 30- and 60-kDa proteins, respectively, to regulate message stability. All of these pathways operate in lung epithelial cells, and endothelial cells regulate uPA expression through a similar pathway. In addition, uPA itself is capable of inducing expression of other components of the fibrinolytic system, including uPAR. This observation defines another feedback loop that could amplify local fibrinolysis and other uPA- or uPAR-mediated cellular responses, including cellular proteolysis, proliferation, and directed cellular migration. CONCLUSIONS: Novel posttranscriptional pathways regulate expression of uPA, uPAR, and plasminogen activator inhibitor-1. uPA itself is capable of inducing other components of the fibrinolytic system. Some or all of these newly recognized pathways are operative in endothelial and parenchymal lung cells and may influence disordered fibrin turnover in the injured lung.

Endothelium, Vascular↗
PubMed2006

The extracellular signal-regulated kinase pathway: an emerging promising target for mood stabilizers.

PURPOSE OF REVIEW: There exists a growing appreciation that, though not classical neurodegenerative disorders, severe mood disorders are associated with regional impairments of structural plasticity and cellular resilience. Exciting recent data suggest that synaptic plasticity probably is involved in mechanisms of actions of mood stabilizers and antidepressants. Notably, the extracellular signal-regulated kinase pathway is a critical 'plasticity pathway' in the brain. The present review summarizes neurobiological, pharmacological, and behavioral data on the role of the extracellular signal-regulated kinase pathway in regulating some of the symptoms of bipolar disorder and as a therapeutically relevant target for mood stabilizers. RECENT FINDINGS: The extracellular signal-regulated kinase pathway is known to mediate neurotrophic actions and synaptic plasticity. Treatment with lithium and valproate activates the extracellular signal-regulated kinase pathway in cultured cells and in prefrontal cortex and hippocampus. In addition, lithium or valproate treatment promotes neurogenesis, neurite growth, and cell survival. The extracellular signal-regulated kinase pathway is also targeted by antipsychotics. Modulation of the central nervous system extracellular signal-regulated kinase pathway induces animal behavioral alterations reminiscent of manic symptoms; these complex behaviors probably depend on the effects of extracellular signal-regulated kinase on discrete brain regions and the presence of other interacting molecules. SUMMARY: The extracellular signal-regulated kinase pathway may represent a novel target for the development of improved therapeutics for bipolar disorder.

Animals↗
PubMed1994

Regulation of the dorsal morphogen by the Toll and torso signaling pathways: a receptor tyrosine kinase selectively masks transcriptional repression.

The dorsal (dl) nuclear gradient initiates the differentiation of the mesoderm, neuroectoderm, and dorsal ectoderm by activating and repressing gene expression in the early Drosophila embryo. This gradient is organized by a Toll signaling pathway that shares many common features with the mammalian IL-1 cytokine pathway. Here we present evidence that a second signaling pathway, controlled by the torso (tor) receptor tyrosine kinase, also modulates dl activity. Evidence is presented that the tor pathway selectively masks the ability of dl to repress gene expression but has only a slight effect on activation. Intracellular kinases that are thought to function downstream of tor, such as D-raf and the rolled MAP kinase, mediate this selective block in repression. Normally, the Toll and tor pathways are both active only at the embryonic poles, and consequently, target genes (zen and dpp) that are repressed in middle body regions are expressed at these sites. Constitutive activation of the tor pathway causes severe embryonic defects, including disruptions in gastrulation and mesoderm differentiation, as a result of misregulation of dl target genes. These results suggest that RTK signaling pathways can control gene expression by antirepression, and that multiple pathways can fine-tune the activities of a single transcription factor.

Animals↗
PubMed1995

The protein kinase C-activated MAP kinase pathway of Saccharomyces cerevisiae mediates a novel aspect of the heat shock response.

The PKC1 gene of budding yeast encodes a homolog of the alpha, beta, and gamma isoforms of mammalian PKC that is proposed to regulate a MAPK-activation pathway. Mutants in this pathway undergo cell lysis resulting from a deficiency in cell wall construction when they attempt to grow at elevated temperatures. We show that the PKC1-regulated pathway is important for induced thermotolerance and that the MPK1 protein kinase (the MAPK of this pathway) is strongly activated by mild heat shock. This activation is sustained during growth at high temperature and is dependent on the function of pathway components proposed to function upstream of MPK1, including PKC1. Expression of genes under the control of known heat shock-inducible promoter elements (HSEs and STREs) was not compromised in PKC1 pathway mutants, indicating that this pathway mediates a novel aspect of the yeast heat shock response. We propose that the heat-induced signal for pathway activation is generated in response to weakness in the cell wall created during growth under thermal stress, perhaps as a result of increased membrane fluidity. Evidence is presented that the mechanism by which the cell detects this weakness is by measuring stretch of the plasma membrane.

Base Sequence↗
PubMed1995

Mutation of RGA1, which encodes a putative GTPase-activating protein for the polarity-establishment protein Cdc42p, activates the pheromone-response pathway in the yeast Saccharomyces cerevisiae.

We have selected yeast mutants that exhibit a constitutively active pheromone-response pathway in the absence of the beta subunit of the trimeric G protein. Genetic analysis of one such mutant revealed that it contained recessive mutations in two distinct genes, both of which contributed to the constitutive phenotype. One mutation identifies the RGA1 locus (Rho GTPase activating protein), which encodes a protein with homology to GAP domains and to LIM domains. Deletion of RGA1 is sufficient to activate the pathway in strains lacking the G beta subunit. Moreover, in wild-type strains, deletion of RGA1 increases signaling in the pheromone pathway, whereas over-expression of RGA1 dampens signaling, demonstrating that Rga1p functions as a negative regulator of the pheromone response pathway. The second mutation present in the original mutant proved to be an allele of a known gene, PBS2, which encodes a putative protein kinase that functions in the high osmolarity stress pathway. The pbs2 mutation enhanced the rga1 mutant phenotype, but by itself did not activate the pheromone pathway. Genetic and two-hybrid analyses indicate that an important target of Rga1p is Cdc42p, a p21 GTPase required for polarity establishment and bud emergence. This finding coupled with recent experiments with mammalian and yeast cells indicating that Cdc42p can interact with and activate Ste20p, a protein kinase that operates in the pheromone pathway, leads us to suggest that Rga1p controls the activity of Cdc42p, which in turn controls the magnitude of signaling in the pheromone pathway via Ste20p.

Amino Acid Sequence↗