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PubMed2005

Aspergillus nidulans HOG pathway is activated only by two-component signalling pathway in response to osmotic stress.

Genome sequencing analyses revealed that Aspergillus nidulans has orthologous genes to all those of the high-osmolarity glycerol (HOG) response mitogen-activated protein kinase (MAPK) pathway of Saccharomyces cerevisiae. A. nidulans mutant strains lacking sskA, sskB, pbsB, or hogA, encoding proteins orthologous to the yeast Ssk1p response regulator, Ssk2p/Ssk22p MAPKKKs, Pbs2p MAPKK and Hog1p MAPK, respectively, showed growth inhibition under high osmolarity, and HogA MAPK in these mutants was not phosphorylated under osmotic or oxidative stress. Thus, activation of the A. nidulans HOG (AnHOG) pathway depends solely on the two-component signalling system, and MAPKK activation mechanisms in the AnHOG pathway differ from those in the yeast HOG pathway, where Pbs2p is activated by two branches, Sln1p and Sho1p. Expression of pbsB complemented the high-osmolarity sensitivity of yeast pbs2Delta, and the complementation depended on Ssk2p/Ssk22p, but not on Sho1p. Pbs2p requires its Pro-rich motif for binding to the Src-homology3 (SH3) domain of Sho1p, but PbsB lacks a typical Pro-rich motif. However, a PbsB mutant (PbsB(Pro)) with the yeast Pro-rich motif was activated by the Sho1p branch in yeast. In contrast, HogA in sskADelta expressing PbsB(Pro) was not phosphorylated under osmotic stress, suggesting that A. nidulans ShoA, orthologous to yeast Sho1p, is not involved in osmoresponsive activation of the AnHOG pathway. We also found that besides HogA, PbsB can activate another Hog1p MAPK orthologue, MpkC, in A. nidulans, although mpkC is dispensable in osmoadaptation. In this study, we discuss the differences between the AnHOG and the yeast HOG pathways.

Amino Acid Motifs↗

PubMed1983

Alternative pathways of glucose utilization in brain: changes in the pattern of glucose utilization and of the response of the pentose phosphate pathway to 5-hydroxytryptamine during aging.

The oxidation of differentially labelled glucose, pyruvate and glutamate in brain slices from rats aged 20 days to 26 months has been studied and the partition of the glucose used into the glycolytic-tricarboxylic acid cycle pathway, the pentose phosphate pathway and the glutamate-GABA shunt has been calculated. Over the time range 4 to 26 months, there is an approximately 20% decrease in the production of CO2 via the glycolytic-tricarboxylic acid cycle route, as there is in the rate of glucose phosphorylation. The glutamate-GABA pathway falls by about 50% over this same time span. The broad activity of the pentose phosphate pathway falls rapidly and cannot be detected in the brains of rats aged 18 months or more, whereas the fully stimulated pathway, i.e. in the presence of the artificial electron acceptor phenazine methosulphate, declines only marginally over this period, falling sharply only after 23 months. The pentose phosphate pathway is stimulated by the presence of 5-hydroxytryptamine and this stimulation appears to increase with age.

Aging↗

PubMed1991

Phase image triangulation of accessory pathways in patients undergoing catheter ablation of posteroseptal pathways.

The outcome of posteroseptal accessory pathway ablation by direct current (DC) shocks delivered just outside the os of the coronary sinus was studied in 21 patients. Electrocardiographic and electrophysiological parameters as well as phase image patterns of equilibrium multiple-gated blood-pool scintigrams were studied to determine their usefulness in predicting the success of ablation. A second free-wall pathway was documented by electrophysiological or surgical findings in six patients, and the value of phase images in detecting this second pathway was studied as well. Ablation was successful in 57%. The cumulative mean energy of DC shocks amounted to 524 +/- 170 joules and was not predictive of ablation outcome, neither was the mean ventriculoatrial (VA) conduction time. The predictive value of the 12-lead maximally preexcited electrocardiogram was poor in the 15 patients with a single posteroseptal bypass tract. A new method to triangulate the site of the earliest phase angle on the atrioventricular (AV) valve plane successfully localized the bypass pathway in 14 of those patients. No specific phase pattern predicted successful ablation except for a symmetrical, concentric peripheral phase progression found to be predictive of ablation success in the four patients who showed this pattern. Phase analysis was able to localize the second, nonposteroseptal pathway in four of six patients. This study showed that a concentric peripheral phase progression in the gated blood-pool scintigrams is predictive for ablation success in patients with posteroseptal pathways. A free-wall localization of the earliest phase angle is suggestive of a second bypass tract in this area.

Adolescent↗

PubMed1989

Regulator and enzyme specificities of the TOL plasmid-encoded upper pathway for degradation of aromatic hydrocarbons and expansion of the substrate range of the pathway.

The TOL plasmid upper pathway operon encodes enzymes involved in the catabolism of aromatic hydrocarbons such as toluene and xylenes. The regulator of the gene pathway, the XylR protein, exhibits a very broad effector specificity, being able to recognize as effectors not only pathway substrates but also a wide variety of mono- and disubstituted methyl-, ethyl-, and chlorotoluenes, benzyl alcohols, and p-chlorobenzaldehyde. Benzyl alcohol dehydrogenase and benzaldehyde dehydrogenase, two upper pathway enzymes, exhibit very broad substrate specificities and transform unsubstituted substrates and m- and p-methyl-, m- and p-ethyl-, and m- and p-chloro-substituted benzyl alcohols and benzaldehydes, respectively, at a high rate. In contrast, toluene oxidase only oxidizes toluene, m- and p-xylene, m-ethyltoluene, and 1,2,4-trimethylbenzene [corrected], also at a high rate. A biological test showed that toluene oxidase attacks m- and p-chlorotoluene, albeit at a low rate. No evidence for the transformation of p-ethyltoluene by toluene oxidase has been found. Hence, toluene oxidase acts as the bottleneck step for the catabolism of p-ethyl- and m- and p-chlorotoluene through the TOL upper pathway. A mutant toluene oxidase able to transform p-ethyltoluene was isolated, and a mutant strain capable of fully degrading p-ethyltoluene was constructed with a modified TOL plasmid meta-cleavage pathway able to mineralize p-ethylbenzoate. By transfer of a TOL plasmid into Pseudomonas sp. strain B13, a clone able to slowly degrade m-chlorotoluene was also obtained.

Enzyme Induction↗

PubMed2003

A Ral guanine exchange factor-Ral pathway is conserved in Drosophila melanogaster and sheds new light on the connectivity of the Ral, Ras, and Rap pathways.

Ras GTPases are central to many physiological and pathological signaling pathways and act via a combination of effectors. In mammals, at least three Ral exchange factors (RalGEFs) contain a Ras association domain and constitute a discrete subgroup of Ras effectors. Despite their ability to bind activated Rap as well as activated Ras, they seem to act downstream of Ras but not downstream of Rap. We have revisited the Ras/Rap-Ral connections in Drosophila melanogaster by using iterative two-hybrid screens with these three GTPases as primary baits and a subsequent genetic approach. We show that (i) the Ral-centered protein network appears to be extremely conserved in human and flies, (ii) in this network, RGL is a functional Drosophila orthologue of RalGEFs, and (iii) the RGL-Ral pathway functionally interacts with both the Ras and Rap pathways. Our data do not support the paradigmatic model where Ral is in the effector pathway of Ras. They reveal a signaling circuitry where Ral is functionally downstream of the Rap GTPase, at odds with the pathways described for mammalian cell lines. Thus, in vivo data show variations in the connectivity of pathways described for cell lines which might display only a subset of the biological possibilities.

Alleles↗

PubMed2003

His electrogram alternans reveal dual atrioventricular nodal pathway conduction during atrial fibrillation: the role of slow-pathway modification.

BACKGROUND: Traditional tools to study dual-pathway atrioventricular nodal (AVN) electrophysiology are not applicable in subjects with permanent atrial fibrillation (AF). The presence of fast-pathway (FP) and slow-pathway (SP) wavefronts and their possible modification remain uncertain in this condition. We demonstrated previously that His electrogram (HE) alternans can determine whether the FP or the SP reaches the His bundle on a beat-by-beat basis. We have now applied this novel index to monitor dual-pathway conduction and the effects of SP modification during AF. METHODS AND RESULTS: In 12 rabbit AVN preparations, HE alternans were confirmed during a standard A(1)A(2) pacing protocol. During AF, in 9 of the 12 hearts, HE alternans indicated the presence of dual pathways. Successful SP modification guided by the HE alternans eliminated the SP, resulting in a predominantly FP conduction during AF in all hearts. This increased the average His-His interval (204+/-14 versus 276+/-51 ms, P<0.001). Morphological studies revealed that SP modification damaged only the posterior extension of the AVN. CONCLUSIONS: We have demonstrated for the first time in rabbits that HE alternans permit "visualization" of dual-pathway electrophysiology and confirmed the presence of both FP and SP wavefronts during AF. This novel index has been used in a selective SP ablation that resulted in a significant slowing of the ventricular rate. HE alternans provide a new insight into the mechanisms of AVN conduction and could guide AVN modification for ventricular rate control in AF clinically.

Animals↗

PubMed1975

"Supernormal conduction" of a premature impulse utilizing the fast pathway in a patient with dual atrioventricular nodal pathways.

Electrophysiological studies with atrial extrastimulus technique suggested the presence of dual atrioventricular (A-V) nodal pathways in a patient with hypothyroidism, as evidenced by a sudden increase of H1-H2 intervals at critical A1-A2 coupling intervals. Following the atrial extrastimulus (A2), a third impulse (A3) occurred spontaneously. During slow pathway conduction of A2, and A3, appearing at a critically timed interval allowed fast pathway conduction, resulting in an earlier than expected QRS (a form of supernormal conduction). This demonstration of fast pathway conduction during slow pathway conduction adds strong evidence for the existence of dual A-V nodal pathways.

Aged↗

PubMed1993

Sodium restriction increases aldosterone biosynthesis by increasing late pathway, but not early pathway, messenger ribonucleic acid levels and enzyme activity in normotensive rats.

To determine whether changes in dietary sodium intake modify the early and/or late pathways of aldosterone biosynthesis, we studied in Sprague-Dawley rats the effect of sodium restriction on early (conversion of cholesterol to pregnenolone) and late (conversion of corticosterone to aldosterone) pathway activity and on the mRNA levels for the enzymes regulating these steps. Sodium restriction increased basal and angiotensin-II-stimulated aldosterone output from isolated zona glomerulosa cells by 5- to 9-fold. This increase in aldosterone output did not appear to be due to changes in the conversion of cholesterol to pregnenolone or in the mRNA levels of the early pathway enzyme, cholesterol side-chain cleavage cytochrome P-450. In contrast, sodium restriction increased the conversion of corticosterone to aldosterone 10-fold and increased by over 10-fold the mRNA levels of the late pathway enzyme aldosterone synthase. Sodium restriction had no effect on zona glomerulosa levels of 11 beta-hydroxylase mRNA. In two other normotensive rats, Dahl salt-resistant and Wistar Kyoto, sodium restriction again specifically increased aldosterone synthase mRNA without altering 11 beta-hydroxylase or cholesterol side-chain cleavage cytochrome P-450 mRNA levels. Thus, it appears that sodium restriction specifically increases late pathway aldosterone synthase mRNA levels, resulting in an increase in enzyme levels, followed by an increase in late pathway activity and an increase in aldosterone output.

Aldosterone↗

PubMed1997

The protein kinase A pathway inhibits c-jun and c-fos protooncogene expression induced by the protein kinase C and tyrosine kinase pathways in cultured human thyroid follicles.

We have previously demonstrated antagonistic interactions between the major signal transduction pathways in human thyroid follicles: TSH acting via protein kinase A (PKA) attenuated phorbol ester [acting via protein kinase C (PKC)] as well as epidermal growth factor (EGF)-protein tyrosine kinase (PTK)-mediated cell proliferation, whereas the PKC and PTK pathways inhibited PKA-mediated cell differentiation. In view of the key role played by the protooncogenes c-jun and c-fos in the cascade of events leading to cell proliferation and differentiation, we examined whether the antagonism we observed between the pathways could be related to changes in the expression of these genes. The experimental model used was the same in vitro system as that used in the above study on cell growth and differentiation: thyroid follicles of human origin cultured in suspension under serum-free conditions. Both EGF (1-50 ng/mL) and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA; 10(-11)-10(-7) mol/L) dose and time dependently stimulated c-jun and c-fos messenger ribonucleic acid (mRNA) expression. The c-jun and c-fos mRNA stimulation elicited by TPA was reduced by the PKC inhibitors, chelerythrine and staurosporine, and could not be mimicked by 4alpha-phorbol 12,13-didecanoate (a phorbol ester that fails to activate PKC), whereas the stimulation induced by EGF was diminished by the PTK inhibitor, genistein. This indicates a PKC- and PTK-mediated pathway triggered by TPA and EGF, respectively. TSH induced an increase in c-jun and c-fos mRNA, which, though significant, was small compared to that elicited by TPA or EGF. Addition of TSH (0.1-0.5 mU/mL), however, to either TPA or EGF dose dependently inhibited the c-jun and c-fos mRNA elicited by these agents. The repressive action of TSH on the effects of TPA and EGF mRNA were mimicked by forskolin and 8-bromo-cAMP, suggesting that the TSH inhibitory action is PKA mediated. The TSH inhibitory action seems to require de novo protein synthesis, as it was abrogated in the presence of cycloheximide. In conclusion, the present study provides novel data on c-jun and c-fos gene expression and their modulation by the major signal transduction pathways operating in human thyrocytes. Moreover, using the same serum-free system of human thyroid follicles cultured with the same agents and at the same doses as in our previous study on cell growth and differentiation, we found the TSH/PKA pathway to inhibit PKC- and EGF/tyrosine kinase-induced c-jun and c-fos mRNA, i.e. antagonistic effects parallel to those previously observed measuring cell proliferation. The findings suggest an association between human thyroid cell proliferation and c-jun and c-fos gene expression.

Cells, Cultured↗

PubMed2000

Neurotrophin-3 sorts to the constitutive secretory pathway of hippocampal neurons and is diverted to the regulated secretory pathway by coexpression with brain-derived neurotrophic factor.

Hippocampal neurons release nerve growth factor (NGF) through the constitutive secretory pathway, thus allowing the protein to be continuously available for promoting nerve cell survival. In contrast, hippocampal neurons use the regulated secretory pathway to process brain-derived neurotrophic factor (BDNF), which alters synaptic activity when released acutely from dense-core vesicles. Thus, understanding how neurons sort and deliver neurotrophins may provide clues to their functions in brain. In this study, we monitored the processing and delivery of neurotrophin-3 (NT-3). Pulse-chase studies, immunocytochemistry, and secretagogue-induced release experiments were performed on cultured hippocampal neurons and AtT-20 cells infected with vaccinia viruses encoding the NT-3 precursor (pro-NT-3). Results show that most newly synthesized NT-3 is released through the constitutive secretory pathway as a result of furin-mediated endoproteolytic cleavage of pro-NT-3 in the trans-Golgi network. Pro-NT-3 can also be diverted into the regulated secretory pathway when cells are treated with alpha1-PDX, a selective inhibitor of furin-like enzymes, or when pro-NT-3 expression is increased by transient transfection methods. In cells coinfected with viruses coding for pro-NT-3 and pro-BDNF, NT-3 is sorted into the regulated pathway, stored in secretory granules, and released in response to extracellular cues together with BDNF, apparently as a result of heterodimerization, as suggested by coimmunoprecipitation data. Taken together, these data show that sorting of the NT-3 precursor can occur in both the constitutive and regulated secretory pathways, which is consistent with NT-3 having both survival-promoting and synapse-altering functions.

Animals↗

PubMed1992

Cross-regulation between G-protein-mediated pathways. Acute activation of the inhibitory pathway of adenylylcyclase reduces beta 2-adrenergic receptor phosphorylation and increases beta-adrenergic responsiveness.

Cross-regulation from the stimulatory to the inhibitory adenylylcyclase pathways has been described (Hadcock, J. R., Ros, M., Watkins, D. C., and Malbon, C. C. (1990) J. Biol. Chem. 265, 14784-14790). More recently, persistent activation (48 h) of the inhibitory adenylylcyclase pathway has been shown to cross-regulate the stimulatory pathway (i) enhancing the maximal response of beta-adrenergic agonits, (ii) increasing the expression of beta-adrenergic receptor, and (iii) reducing the ED50 for the isoproterenol-stimulated response by 50-fold (Hadcock, J. R., Port, J. D., and Malbon, C. C. (1991) J. Biol. Chem. 266, 11915-11922). Here, we report that short term activation (60 min) of the inhibitory adenylylcyclase pathway of hamster smooth muscle DDT1MF-2 cells with the A1-adenosine receptor agonist N6-phenylisopropyladenosine (PIA) likewise enhances the stimulatory adenylylcyclase response to the beta-adrenergic agonist isoproterenol. The PIA effect was exerted at the level of the receptor, i.e., the beta-adrenergic receptor-mediated response was enhanced, whereas the guanosine 5'-O-(thiotriphosphate)- and forskolin-stimulated adenylylcyclase activities were largely unaffected. In contrast to longer term persistent activation of the inhibitory pathway, receptor number and affinity for 125I-labeled cyanopindolol were unaffected. Metabolic labeling of cells with [32P]orthophosphate and immuneprecipitation of beta-adrenergic receptors detected phosphorylation of the receptor in unstimulated cells and marked phosphorylation in cells challenged with epinephrine. When cells were challenged short term with PIA, the basal state of beta-adrenergic receptor phosphorylation was reduced by 75%. Treating cells with PIA in combination with the cAMP analog 8-(4-chlorophenylthio)adenosine cyclic AMP attenuated the enhanced receptor-mediated adenylylcyclase response observed in cells treated with PIA alone. These data suggest that short term cross-regulation from the inhibitory to stimulatory adenylylcyclase pathways results in the following: (i) decreased intracellular cAMP levels and protein kinase A activity, (ii) reduced phosphorylation of the beta 2-adrenergic receptor in the "basal" (i.e. unstimulated) state, and (iii) enhanced receptor-mediated activation of Gs.

Adenylyl Cyclases↗

PubMed1997

Immunoelectron microscopic demonstration of regulated pathway for calcitonin and constitutive pathway for carcinoembryonic antigen in the same cells of human medullary carcinomas of thyroid glands.

The human medullary carcinomas are well known to secrete calcitonin (CT) as a neuroendocrine peptide and carcinoembryonic antigen (CEA) as a serum protein that is integrated into the cell membrane. This ultrastructural study is designed to elucidate whether CT and CEA are secreted via two different intracellular secretory pathways, a regulated pathway and a constitutive pathway. The immunoelectron microscopic postembedding method, performed on four cases of the human medullary carcinomas of the thyroid using plastic embedding material, disclosed two distinct different localization patterns for CT and CEA. CT was localized exclusively in dense cored secretory granules. CEA was present in the cell membrane and in the secretory vesicles. The secretory granules were completely negative for CEA. The trans-Golgi networks were also positive for CT and CEA. Electron microscopic double staining confirmed these localization in the same carcinoma cells. These observations suggest the presence of two distinct pathways in the endocrine cancer cells, i.e., the regulated pathway for CT and the constitutive pathway for CEA.

Biological Transport↗

PubMed2002

Which came first, the lectin/classical pathway or the alternative pathway of complement?

It is a widely accepted canon of immunology that the alternative pathway is more primitive and hence older in evolutionary terms than the lectin/classical pathway. This idea has been reinforced by the discovery of "C3" and "factor B" proteins in invertebrate species. However, it is clear that the gene duplications which gave rise to C3/C4/C5 and factor B/C2 occurred in the vertebrate lineage. Hence, the naming of the invertebrate proteins may be based on preconceptions rather than on solid structural or functional evidence. Lectins and associated MASP/C1r/C1s-like proteins have been found in invertebrates, while factor D, the defining component of an alternative pathway, has so far been found only in the bony fish and higher species. It is a principle of Darwinian evolution that complex systems develop through small sequential steps. It is possible to imagine such a series of steps for the evolution of a lectin pathway, involving as it does recognition of non-self. It is difficult to see how the alternative pathway, which lacks a recognition molecule, could have evolved without the prior development of control proteins to protect self from attack.

Animals↗

PubMed2006

Plasticity within striatal direct pathway neurons after neonatal dopamine depletion is mediated through a novel functional coupling of serotonin 5-HT2 receptors to the ERK 1/2 map kinase pathway.

Dysfunction within the striatal direct and indirect projecting systems arises after 6-hydroxydopamine (6-OHDA)-induced dopamine depletion, highlighting the central regulatory function of dopamine in motor systems. However, the striatal 5-hydroxytryptamine (5-HT) innervation remains intact after 6-OHDA lesions, suggesting that the 5-HT system may contribute to the lesion-induced dysfunction, or alternatively, it may adapt and compensate for the dopamine deficit. Neonatal 6-OHDA lesions actually give rise to a 5-HT axonal hyperinnervation within the dorsal striatum, further reinforcing the idea that the 5-HT system plays a central role in striatal function after dopamine depletion. Here we show that neonatal but not adult 6-OHDA lesions result in a novel coupling of 5-HT2 receptors to the ERK1/2/MAP Kinase pathway, a signaling cascade known to regulate neuronal plasticity. Chloroamphetamine-induced 5-HT release or direct stimulation of striatal 5-HT2 receptors via the 5-HT2 agonist DOI, produced robust ERK1/2 phosphorylation throughout the dorsal striatum of neonatal lesioned animals, a response not observed within the intact striatum. Pretreatment with the select 5-HT2 receptor antagonist Ketanserin blocked DOI-induced ERK1/2 phosphorylation. This drug-induced ERK1/2 phosphorylation was subsequently shown to be restricted to direct pathway striatal neurons. Our data show that adaptation of direct pathway neurons after neonatal 6-OHDA lesions involves coupling of 5-HT2 receptors to the ERK1/2/MAP Kinase cascade, a pathway not typically active in these neurons. Because dopamine-mediated signaling is redundant after 6-OHDA lesions, 5-HT-mediated stimulation of the ERK1/2/MAP Kinase pathway may provide an alternative signaling route allowing the regulation of neuronal gene expression and neuronal plasticity in the absence of dopamine.

Animals↗

PubMed1998

The antigen presentation pathway in medullary thymic epithelial cells, but not that in cortical thymic epithelial cells, conforms to the endocytic pathway.

Murine medullary thymic epithelial cells (mTEC), but not cortical thymic epithelial cells (cTEC), are able to present a soluble antigen, ovalbumin, to helper T cells (Mizuochi, T. et al., J. Exp. Med. 1992. 175: 1601-1605). This functional difference between the mTEC and the cTEC is particularly important when we consider the thymic selection of the T cell repertoire. In the previous report, we proposed that mTEC and cTEC utilize two distinct antigen processing/presenting pathways (Kasai, M. et al., Eur. J. Immunol. 1996. 26: 2101-2107). In this report, we further confirmed this difference by analyzing (a) localization of MHC class II, H2-DM, and invariant chain (li) molecules, (b) the biochemical nature of MHC class II molecules, (c) the sensitivity of MHC class II alphabeta heterodimer formation to concanamycin A, a vacuolar H+-ATPase inhibitor, and (d) the subcellular distribution of MHC class II, H2-DM, and li molecules, in both TEC. Our results demonstrated that, in the mTEC, MHC class II, H2-DM and li molecules gain access to the endocytic pathway, where the luminal condition is acidic and thus li molecules are efficiently degraded and H2-DM molecules function well. In the cTEC, however, such molecules seemed to gain access to an alternative transport pathway, e.g. a secretory pathway, where the luminal condition is not fully acidic. These two distinct antigen processing pathways may account for the functional difference between mTEC and cTEC.

Amino Acid Sequence↗

PubMed2005

A biosynthetic pathway to isovaleryl-CoA in myxobacteria: the involvement of the mevalonate pathway.

A biosynthetic shunt pathway branching from the mevalonate pathway and providing starter units for branched-chain fatty acid and secondary metabolite biosynthesis has been identified in strains of the myxobacterium Stigmatella aurantiaca. This pathway is upregulated when the branched-chain alpha-keto acid dehydrogenase gene (bkd) is inactivated, thus impairing the normal branched-chain amino acid degradation process. We previously proposed that, in this pathway, isovaleryl-CoA is derived from 3,3-dimethylacrylyl-CoA (DMA-CoA). Here we show that DMA-CoA is an isomerization product of 3-methylbut-3-enoyl-CoA (3MB-CoA). This compound is directly derived from 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) by a decarboxylation/ dehydration reaction resembling the conversion of mevalonate 5-diphosphate to isopentenyl diphosphate. Incubation of cell-free extracts of a bkd mutant with HMG-CoA gave product(s) with the molecular mass of 3MB-CoA or DMA-CoA. The shunt pathway most likely also operates reversibly and provides an alternative source for the monomers of isoprenoid biosynthesis in myxobacteria that utilize L-leucine as precursor.

Acyl Coenzyme A↗

PubMed2004

Differential chemokine activation of CC chemokine receptor 1-regulated pathways: ligand selective activation of Galpha 14-coupled pathways.

Chemokines regulate the chemotaxis, development, and differentiation of many cell types enabling the regulation of routine immunosurveillance and immunological adaptation. CC chemokine receptor 1 (CCR1) is the target of 11 chemokines. This promiscuity of receptor-ligand interactions and the potential for functional redundancy has led us to investigate the selective activation of CCR1-coupled pathways by known CCR1 agonists. Chemokines leukotactin-1, macrophage inflammatory protein (MIP)-1alpha, monocyte chemotactic peptide (MCP)-3, RANTES, and MIP-1delta all inhibited adenylyl cyclase activity in cells transiently transfected with CCR1. In contrast, only MIP-1delta was unable to signal via G14-, G16- or chimeric 16z44-coupled pathways. In a stable cell line expressing CCR1 and Galpha14, all of these five chemokines along with hemofiltrate CC chemokine (HCC)-1 and myeloid progenitor inhibitory factor (MPIF)-1 were able to stimulate G(i/o)-coupled pathways, but MIP-1delta, HCC-1 and MPIF-1 were unable to activate G14-mediated stimulation of phospholipase Cbeta activity. In addition, MIP-1delta was unable to promote the phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase. This suggests that different chemokines are able to selectively activate CCR1-coupled pathways, probably because of different intrinsic ligand efficacies. CCR1 and Galpha14 or Galpha16 are co-expressed in several cell types and we hypothesize that selective activation of chemokine receptors provides a mechanism by which chemokines are able to fine-tune intracellular signaling pathways.

Animals↗

PubMed2003

Cysteine proteases are the major beta-secretase in the regulated secretory pathway that provides most of the beta-amyloid in Alzheimer's disease: role of BACE 1 in the constitutive secretory pathway.

This article focuses on beta-amyloid (Abeta) peptide production and secretion in the regulated secretory pathway and how this process relates to accumulation of toxic Abeta in Alzheimer's disease. New findings are presented demonstrating that most of the Abeta is produced and secreted, in an activity-dependent manner, through the regulated secretory pathway in neurons. Only a minor portion of cellular Abeta is secreted via the basal, constitutive secretory pathway. Therefore, regulated secretory vesicles contain the primary beta-secretases that are responsible for producing the majority of secreted Abeta. Investigation of beta-secretase activity in regulated secretory vesicles of neuronal chromaffin cells demonstrated that cysteine proteases account for the majority of the beta-secretase activity. BACE 1 is present in regulated secretory vesicles but provides only a small percentage of the beta-secretase activity. Moreover, the cysteine protease activities prefer to cleave the wild-type beta-secretase site, which is relevant to the majority of AD cases. In contrast, BACE 1 prefers to cleave the Swedish mutant beta-secretase site that is expressed in a minor percentage of the AD population. These new findings lead to a unifying hypothesis in which cysteine proteases are the major beta-secretases for the production of Abeta in the major regulated secretory pathway and BACE 1 is the beta-secretase responsible for Abeta production in the minor constitutive secretory pathway. These results indicate that inhibition of multiple proteases may be needed to decrease Abeta production as a therapeutic strategy for Alzheimer's disease.

Alzheimer Disease↗