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Biomedical subjects

B Ritter

Publications and source records attributed to B Ritter.

At least 19 recordsLinked to original sources
PubMed2002

Differential ontogeny of GABA(B)-receptor-mediated pre- and postsynaptic modulation of GABA and glycine transmission in respiratory rhythm-generating network in mouse.

Rhythm generation in mature respiratory networks is influenced strongly by synaptic inhibition. In early neonates, GABA(A)-receptor- and glycine-receptor-mediated inhibition is not present, thus the question arises as to whether GABA(B)-receptor-mediated inhibition plays an important role. Using brainstem slices of neonatal mice (postnatal day, P0-P15), we analysed the role of GABA(B)-mediated modulation of GABA and glycine synaptic transmission in the respiratory network. Blockade of GABA uptake by nipecotic acid (0.25-2 mM) reduced the respiratory frequency. This reduction was prevented by the selective GABA(B) receptor antagonist CGP55845A (CGP) alone at P0-P3, but by bicuculline as well as CGP at P7-P15. Blockade of GABA(B) receptors by CGP increased the respiratory frequency at P0-P3, whereas it caused a reduction of frequency in older animals. The effect of CGP on respiratory frequency was diminished in the presence of bicuculline and strychnine in older but not in younger animals. The relative contribution of GABA(B)-receptor-mediated pre- and postsynaptic modulation was examined by analysing the effect of GABA(B) receptors on spontaneous and miniature IPSCs. In younger animals (P0-P3), the GABA(B) receptor agonist baclofen had no detectable effect on IPSC frequency, but caused a significant decrease in the amplitude. In older animals (P7-P15), baclofen decreased both the frequency and amplitude of spontaneous and miniature IPSCs. These results demonstrate that GABA(B)-receptor-mediated postsynaptic modulation plays an important role in the respiratory network from P0 on. GABA(B)-receptor-mediated presynaptic modulation develops with a longer postnatal latency, and becomes predominant within the first postnatal week.

Aging↗
PubMed2001

The Ras/Rac guanine nucleotide exchange factor mammalian Son-of-sevenless interacts with PACSIN 1/syndapin I, a regulator of endocytosis and the actin cytoskeleton.

Mammalian Son-of-sevenless (mSos) functions as a guanine nucleotide exchange factor for Ras and Rac, thus regulating signaling to mitogen-activated protein kinases and actin dynamics. In the current study, we have identified a new mSos-binding protein of 50 kDa (p50) that interacts with the mSos1 proline-rich domain. Mass spectrometry analysis and immunodepletion studies reveal p50 as PACSIN 1/syndapin I, a Src homology 3 domain-containing protein functioning in endocytosis and regulation of actin dynamics. In addition to PACSIN 1, which is neuron-specific, mSos also interacts with PACSIN 2, which is expressed in neuronal and nonneuronal tissues. PACSIN 2 shows enhanced binding to the mSos proline-rich domain in pull-down assays from brain extracts as compared with lung extracts, suggesting a tissue-specific regulation of the interaction. Proline to leucine mutations within the Src homology 3 domains of PACSIN 1 and 2 abolish their binding to mSos, demonstrating the specificity of the interactions. In situ, PACSIN 1 and mSos1 are co-expressed in growth cones and actin-rich filopodia in hippocampal and dorsal root ganglion neurons, and the two proteins co-immunoprecipitate from brain extracts. Moreover, epidermal growth factor treatment of COS-7 cells causes co-localization of PACSIN 1 and mSos1 in actin-rich membrane ruffles, and their interaction is regulated through epidermal growth factor-stimulated mSos1 phosphorylation. These data suggest that PACSINs may function with mSos1 in regulation of actin dynamics.

Actins↗
PubMed2001

Phosphorylation of a synaptic vesicle-associated protein by an inositol hexakisphosphate-regulated protein kinase.

Despite the fact that inositol hexakisphosphate (InsP(6)) is the most abundant inositol metabolite in cells, its cellular function has remained an enigma. In the present study, we present the first evidence of a protein kinase identified in rat cerebral cortex/hippocampus that is activated by InsP(6). The substrate for the InsP(6)-regulated protein kinase was found to be the synaptic vesicle-associated protein, pacsin/syndapin I. This brain-specific protein, which is highly enriched at nerve terminals, is proposed to act as a molecular link coupling components of the synaptic vesicle endocytic machinery to the cytoskeleton. We show here that the association between pacsin/syndapin I and dynamin I can be increased by InsP(6)-dependent phosphorylation of pacsin/syndapin I. These data provide a model by which InsP(6)-dependent phosphorylation regulates synaptic vesicle recycling by increasing the interaction between endocytic proteins at the synapse.

Amino Acid Sequence↗
PubMed2000

Protein expression patterns of identified neurons and of sprouting cells from the leech central nervous system.

It has previously been shown that cephalic, segmental, and caudal ganglia from the medicinal leech show differences in their protein composition. Here we studied whether the neuronal reorganization that occurs in cultured segmental ganglia from the medicinal leech is accompanied by detectable changes in the protein expression pattern. Using silver-stained two-dimensional gels we showed that after 5 and 12 days in culture changes in the protein patterns can be detected in isolated ganglia. The changes observed in the two-dimensional gels occurred concomitantly with a sprouting of serotoninergic neurites and a decreased transmitter content of dopaminergic neurites as shown by using the glyoxylic acid condensation reaction. In addition, we present evidence that Retzius cells, which can be identified by their characteristic morphology and action potential waveform, exhibit biochemically unique properties with respect to their protein expression pattern.

Animals↗
PubMed2000

Early postnatal maturation of GABAA-mediated inhibition in the brainstem respiratory rhythm-generating network of the mouse.

It is well established that GABAA-mediated postsynaptic potentials are excitatory in many brain regions during embryonic and early postnatal life. The pre-Bötzinger complex (PBC) in the brainstem is an essential component of the respiratory rhythm-generating network, where GABAA-mediated inhibition plays a critical role in generating a stable respiratory rhythm in adult animals. In the present study, using the perforated patch technique, we investigated the maturation of GABAA receptor-mediated effects on rhythmically active PBC neurons and on the motor output in slice preparations from P0-15 neonatal mice. The reversal potential of GABAA receptor-mediated current (EGABA-A) switched from depolarizing to hyperpolarizing within the first postnatal week. EGABA-A was -13.7 +/- 9.8 mV at P0, then it changed to -44.8 +/- 7.0 mV at P2 and -71.5 +/- 6.8 mV at P4. Perfusion of bicarbonate-free saline has no detectable influence on EGABA-A, indicating that a lack of Cl- extrusion during P0-3 is mainly responsible for early GABAA-ergic excitation. At the network level, blockade of GABAA receptors with bicuculline did not significantly change the frequency of rhythmic bursts recorded from hypoglossal nerve roots before P3, whereas it increased the coefficient of variation. After P3, bicuculline increased burst frequency with little effect on the coefficient of variation. Thus, chloride-mediated inhibition, which appears in PBC neurons after P3, coincides with the appearance of GABAA-mediated modulation of the respiratory rhythm. GABAA receptor-activated inhibition may therefore be necessary for frequency modulation in the respiratory network beginning on the fourth postnatal day in the mouse brainstem.

Action Potentials↗
PubMed2000

All three PACSIN isoforms bind to endocytic proteins and inhibit endocytosis.

The PACSINs are a family of cytoplasmic phosphoproteins that play a role in vesicle formation and transport. We report the cloning and cDNA sequencing of PACSIN 3 and the analysis of all three PACSIN isoforms with regard to tissue distribution, ligand binding properties and influence on endocytosis. PACSIN 3 differs from the other family members in having a short proline-rich region and lacking asparagine-proline-phenylalanine motifs. In contrast to the neurospecific PACSIN 1 and the ubiquitously expressed PACSIN 2, PACSIN 3 is mainly detected in lung and muscle tissues. All isoforms potentially oligomerize and bind to dynamin, synaptojanin 1 and N-WASP via their Src homology 3 domains. The PACSIN proteins colocalize with dynamin, but not with clathrin, implying a specific role with a distinct subpopulation of dynamin at defined cellular sites. Transferrin endocytosis is blocked in a dose-dependent manner in cells overexpressing the PACSIN variants, but the inhibitory effect can be abolished by mutating specific amino acid residues in the Src homology 3 domains. These characteristics of the PACSIN protein family suggest a general function in recruitment of the interacting proteins to sites of endocytosis.

Adaptor Proteins, Signal Transducing↗
PubMed1999

The p38 MAP kinase pathway signals for cytokine-induced mRNA stabilization via MAP kinase-activated protein kinase 2 and an AU-rich region-targeted mechanism.

Stabilization of mRNAs contributes to the strong and rapid induction of genes in the inflammatory response. The signaling mechanisms involved were investigated using a tetracycline-controlled expression system to determine the half-lives of interleukin (IL)-6 and IL-8 mRNAs. Transcript stability was low in untreated HeLa cells, but increased in cells expressing a constitutively active form of the MAP kinase kinase kinase MEKK1. Destabilization and signal-induced stabilization was transferred to the stable beta-globin mRNA by a 161-nucleotide fragment of IL-8 mRNA which contains an AU-rich region, as well as by defined AU-rich elements (AREs) of the c-fos and GM-CSF mRNAs. Of the different MEKK1-activated signaling pathways, no significant effects on mRNA degradation were observed for the SAPK/JNK, extracellular regulated kinase and NF-kappaB pathways. Selective activation of the p38 MAP kinase (=SAPK2) pathway by MAP kinase kinase 6 induced mRNA stabilization. A dominant-negative mutant of p38 MAP kinase interfered with MEKK1 and also IL-1-induced stabilization. Furthermore, an active form of the p38 MAP kinase-activated protein kinase (MAPKAP K2 or MK2) induced mRNA stabilization, whereas a negative interfering MK2 mutant interfered with MAP kinase kinase 6-induced stabilization. These findings indicate that the p38 MAP kinase pathway contributes to cytokine/stress-induced gene expression by stabilizing mRNAs through an MK2-dependent, ARE-targeted mechanism.

3' Untranslated Regions↗
PubMed1999

PACSIN 2, a novel member of the PACSIN family of cytoplasmic adapter proteins.

The PACSIN-related proteins are cytoplasmic adapter proteins with a common arrangement of domains and conserved regions. Here we report the cloning, sequencing, and expression of PACSIN 2, a novel member of the PACSIN protein family and accordingly rename the original PACSIN to PACSIN 1. The sequences of the murine and human cDNAs reveal an open reading frame encoding a putative protein of 486 residues. Despite its high sequence similarity to PACSIN 1, PACSIN 2 is encoded by distinct transcripts in human and mouse, in particular displaying a ubiquitous expression pattern. Immunofluorescence microscopy of PACSIN 2-transfected NIH3T3 fibroblasts reveal a broad, vesicle-like cytoplasmic staining. In contrast to FAP52, another PACSIN-related protein derived from chicken brain, PACSIN 2 could not be detected at focal contacts. Taken together, these findings suggest that PACSIN 2 is a novel PACSIN isoform with similar domain and motif arrangement, but an unrestricted expression pattern, which may participate in the organization of the actin cytoskeleton and the regulation of vesicular traffic.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Health effects of sulfur-related environmental air pollution. V. Lung structure.

The lungs of 8 male beagle dogs were examined morphologically and morphometrically after exposure for 13 mo to a respirable sulfur(IV) aerosol at a mass concentration of 1.53 mg m(-3) (16.5 h/day), and to an acidic sulfate aerosol carrying 15.2 micromol m(-3) hydrogen ions into the lungs (6 h/day). An additional eight dogs served as unexposed controls. Standard morphometric analyses of both the surface epithelia of the conducting airways and the alveolar region were performed. These analyses showed no difference between the exposure group and control group. However, there was a tendency to an increase in the volume density of bronchial glands in the exposure group. Five of eight exposed animals showed thickened ridges (knob-like structures) at the entrance to alveoli in the alveolar duct and alveolar sac. Transmission electron microscopy revealed that the thickening was mainly due to type II cell proliferation. As the previous experiment using sulfite aerosol only showed no alterations in the proximal alveolar regions, the changes observed may be considered as effects of acidic sulfate aerosol alone or in combination with sulfite. These findings suggest that sulfur aerosols have the potential to induce epithelial alterations in the proximal alveolar region, which is a primary target for air pollutants.

Aerosols↗
PubMed1998

The respiratory bronchiole of beagle dogs: structural characteristics.

The centriacinar regions are a central site of lung diseases and they are also considered to be susceptible to air pollutants. Dogs as well as humans and monkeys possess several generations of respiratory bronchioles. Commonly used small laboratory animals, however, have either no, or at most, a single short generation. Therefore, it is assumed that the response to air pollutants differs among animal species according to the presence or absence of the respiratory bronchiole. Although the conducting airways and alveolar regions have been well examined, morphological details of the respiratory bronchiole remain to be elucidated. To better understand the architecture of the respiratory bronchiole, we investigated this region of beagle dogs by means of serial sections of paraffin tissues. This study shows that respiratory bronchioles of beagle dogs consist of up to five generations. Branching patterns of the respiratory bronchiole of beagle dogs were comparable to those of humans. The surface of the respiratory bronchiole is comprised of the bronchiolar epithelial lining and alveolar outpocketings. The lining cells of beagle dogs are mainly nonciliated cells (Clara cells) whereas ciliated cells are very rare.

Animals↗
PubMed1996

Morphometric evaluation of bronchial glands of beagle dogs.

Using lung tissues of beagle dogs, we developed a method for objective estimation of bronchial glands. Defined generations (5th, 10th, 15th and 20th) of bronchi were collected according to the microdissection method by Plopper et al. (1983) [1]. Transverse sections were prepared for both light microscopic and electron microscopic studies. The point counting using prints made by a video copy processor was performed for estimation of the volume density of bronchial glands. Bronchial glands were observed throughout the canine bronchial tree. Moreover, a distinct difference was found in the volume density of bronchial glands depending on the lobe examined and the generation number. Recently, we performed a long-term inhalation study using beagle dogs in order to elucidate toxic effects of sulfur(IV) and acidic sulfate aerosols (Heyder et al., 1994) [2]. In addition to the quantitative analysis of surface epithelia, the volume density of submucosal glands in the bronchial wall was measured according to the method described above. As preliminary result, there was a tendency to an increased volume density of glands in the exposure group. Detailed quantitative evaluation of bronchial glands may enable detection of finite changes induced by low level concentrations of air pollutants.

Air Pollutants↗
PubMed1995

Antianginal effect of conventional and controlled release diltiazem in stable angina pectoris.

Two preparations of diltiazem, controlled release (CR) given twice a day (b.i.d.) and plain given 4 times a day (q.i.d.), were compared in a multicentre, double-blind, crossover study in 41 patients with stable angina pectoris. Therapeutic efficacy was assessed with maximal exercise tests, patient recordings on nitroglycerine consumption and angina attacks. No significant differences between the CR and plain tablets were seen in any of the efficacy variables. Maximal workload significantly increased from 127 W on placebo to 146 W on CR tablets and to 147 W on plain tablets. Anginal attacks/week significantly decreased from 11.7 on placebo to 4.9 on CR tablets and to 5.0 on plain tablets. Consumption of nitroglycerine tablets/week significantly decreased from 6.3 on placebo to 2.6 and to 3.4 on CR and plain-tablets, respectively. The number or the seriousness of the adverse events did not differ between the groups. The results imply that diltiazem CR b.i.d. is equally potent and safe as conventional diltiazem q.i.d. in the control of stable angina pectoris.

Aged↗