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At least 613 records · Page 34Linked to original sources
PubMed1995

Developmentally expressed Ca(2+)-sensitive adenylyl cyclase activity is disrupted in the brains of type I adenylyl cyclase mutant mice.

The type I Ca(2+)-sensitive adenylyl cyclase has been implicated in several forms of synaptic plasticity in vertebrates. Mutant mice in which this enzyme was inactivated by targeted mutagenesis show deficient spatial memory and altered long term potentiation (Wu, Z. L., Thomas, S. A., Villacres, E. C., Xia, Z., Simmons, M. L., Chavkin, C., Palmiter, R. D., and Storm, D. R. (1995) Proc. Natl Acad Sci. U. S. A. 92, 220-224). Long term potentiation in the CA1 region of the rat hippocampus develops during the first 2 weeks after birth and reaches maximal expression at postnatal day 15 with a gradual decline at later stages of development. Here we report that Ca(2+)-stimulated adenylyl cyclase activity in rat hippocampus, cerebellum, and cortex increases significantly between postnatal days 1-16. This increase appears to be due to enhanced expression of type I adenylyl cyclase rather than type VIII adenylyl cyclase, the other adenylyl cyclase that is directly stimulated by Ca2+ and calmodulin. Type I adenylyl cyclase mRNA in the hippocampus increased 7-fold during this developmental period. The developmental expression of Ca(2+)-stimulated adenylyl cyclase activity in mouse brain was attenuated in mutant mice lacking type I adenylyl cyclase. Changes in expression of the type I adenylyl cyclase during the period of long term potentiation development are consistent with the hypothesis that this enzyme is important for neuroplasticity and spatial memory in vertebrates.

Adenylyl Cyclases↗
PubMed1993

Muramyl peptides augment the in vitro and in vivo cytostatic activity of canine plastic-adherent mononuclear cells against canine osteosarcoma cells.

A tumor cytostasis assay was developed that measured the effect of the immunomodulator muramyl dipeptide (MDP) on the in vitro cytostatic activity of canine plastic-adherent mononuclear cells. Mononuclear cells were isolated from the peripheral blood of healthy Beagle donors and allowed to adhere to a 96-well microtiter plate. The adherent cell population was characterized by cell morphology, non-specific esterase staining, and flow microfluorometry to be approximately 42% monocytes, 49% lymphocytes, and 8% eosinophils. Canine plastic-adherent mononuclear cells spontaneously caused cytostasis of D-17 canine osteosarcoma target cell proliferation. The spontaneous cytostatic activity of adherent mononuclear cells was significantly augmented by exposure to MDP or to lipopolysaccharide (LPS), with maximal cytostatic activity being observed after combined exposure to MDP and LPS. Mononuclear cell cytostasis toward D-17 canine osteosarcoma and A375 human melanoma cells was enhanced (P < 0.05) when normal dogs were administered liposome-encapsulated muramyl tripeptide phosphatidylethanolamine, a lipophilic derivative of MDP, by intravenous injection.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2004

A single-chain tetradomain glycoprotein hormone analog elicits multiple hormone activities in vivo.

We previously demonstrated that genetically linking one or more of the glycoprotein hormone-specific beta subunit genes to the common alpha subunit resulted in single-chain analogues that were bioactive in vitro. The ability of such large structures to bind their cognate receptors with high affinity supported the hypothesis that extensive flexibility exists between the ligand and receptor to establish a functional complex. To further characterize the extent of this conformational flexibility, we engineered a single-chain analogue that consists of sequentially linked thyroid-stimulating hormone (TSH) beta, follicle-stimulating hormone (FSH) beta, and chorionic gonadotropin (CG) beta subunits to the alpha subunit and expressed this chimera in transfected CHO (Chinese hamster ovary) cells. Because the four subunits are genetically linked and expressed as a single-chain, this analogue presumably lacks significant native structural features of the individual heterodimers. However, it exhibited FSH, CG, and TSH activities in vitro. Here, we test whether this nonnative structure would be stable in vivo and thus biologically active. Using a variety of bioassay protocols, we demonstrate that the analogue elicits multihormone activities when injected in vivo. First, treatment with the analogue caused increases in ovarian and uterine weights and resulted in elevated serum estradiol. Second, the analogue-stimulated ovarian follicle growth and pharmacologically rescued in vivo FSH deficiency similar to recombinant human FSH or equine CG (eCG) as confirmed by induction of aromatase in the ovaries of FSHbeta knockout mice. Third, in a superovulation protocol, when primed with eCG, the analogue elicited a dose-dependent ovulatory response comparable with that by native heterodimeric human CG. Finally, the analogue-stimulated thyroxin production in hypothyroid mice similar to the pituitary-derived human TSH standard. Based on these data, we conclude that a single-chain tetradomain glycoprotein hormone analogue, despite its presumed altered conformation, is stable and biologically active in vivo. Our results establish the permissiveness and conformational plasticity with which the glycoprotein hormones are recognized in vivo by their target cell receptors.

Animals↗
PubMed1985

Suppressor cell activity of cells infiltrating rat renal allografts prolonged by perioperative administration of extracted histocompatibility antigen and cyclosporine.

Suppressor T cells were identified in situ within renal allografts of hosts rendered unresponsive by perioperative administration of donor histocompatibility antigen, which was extracted from donor spleen cells with 3M KCl, combined with cyclosporine (Ag-CsA). Infiltrating cells harvested from Buffalo (BUF, RT1b) renal allografts ten days after transplantation into Wistar-Furth (WFu, RT1u) rats treated with a single i.v. injection of 5 mg 3M KCl-extracted donor antigen (Ag) combined with a three day course of CsA inhibited the mixed lymphocyte culture (MLC) reaction between normal responder WFu and irradiated BUF cells (79.3% suppression, P less than 0.001), but not third-party Brown-Norway (BN, RT1n) stimulator cells (-5.4% suppression, NS). The suppressor effect was not due to cytolysis: the infiltrating cells did not lyse 51Cr-labeled concanavalin A (Con-A) blastoid BUF cells, as did the infiltrating cells from nonimmunosuppressed recipient allografts undergoing rejection responses toward BUF (49% specific cytolysis, E/T = 25), but not third-party BN, target cells five days after transplantation. The suppressor cells were nonadherent to plastic dishes and sensitive to monoclonal antibodies (Mab) W3/13 HLK (pan-T cells: % suppressor -17.9) or cytotoxic/suppressor cells with Mab OX-8 (-5.0% suppression), but not W3/25 (helper; 48.6% suppression, P less than 0.025). Moreover, adoptive transfer of 10(6) infiltrating cells from Ag-CsA-treated recipient allografts into virgin WFu hosts prolonged primary BUF graft survival from 7.2 to 14.0 days (P less than 0.05), but not third-party BN grafts (treated MST = 11.9 +/- 3.9 days versus untreated MST = 11.0 +/- 2.9 days, NS). On the other hand, infiltrating cells from CsA-only-treated recipient allografts could not transfer this effect (MST = 7.7 +/- 0.5 days, P less than 0.01). Finally, retransplantation of the BUF allograft from the Ag-CsA treated rat to a syngeneic, virgin WFu host ten days after primary transplantation yielded prolonged survival with MST 11.4 +/- 2.3 versus control primary graft survival in untreated animals of 7.2 +/- 0.6 days (P less than 0.001). BUF allografts from treated WFu hosts retransplanted into third-party BN rats did not display prolonged graft survival (MST = 9.2 +/- 1.1 days) compared with primary BUF grafts in untreated BN recipients (MST = 9.2 +/- 2.0 days, NS). The presence of suppressor T cells both in the spleen and in situ in renal allografts following Ag-CsA treatment suggests that local mechanisms may augment systemic elements to control the generation of alloimmunity.

Animals↗
PubMed2005

Enhanced episodic-like memory and kindling epilepsy in a rat model of tuberous sclerosis.

Tuberous sclerosis complex (TSC) is a common neurological autosomal-dominant syndrome caused by mutations in the TSC1 or TSC2 genes. TSC starts in early childhood and is characterized by cerebral hamartomas (benign tumours), severe epilepsy and cognitive deficits such as mental retardation and autism. The hamartomas are characterized by loss of the remaining wild-type TSC allele, and clinical data implicate cerebral hamartomas in the generation of epileptic seizures, which may play a significant role in the development of mental retardation. The TSC2 mutation predicts alterations in mitogen-associated protein kinase (MAPK) and, together with the TSC1 mutation, in mammalian target of rapamycin (mTOR) signalling pathways. Both pathways are involved in neuronal plasticity. We therefore hypothesized that the heterozygous mutation itself, besides cerebral hamartomas, contributes to the pathogenesis of cognitive deficits and possibly also epilepsy. Here, we show that young adult TSC2+/- rats, which are virtually free of cerebral hamartomas, exhibit enhanced episodic-like memory and enhanced responses to chemically-induced kindling. The activation of cyclic adenosine monophosphate (cAMP) in the hippocampus results in stronger induction of phospho-p42-MAPK in TSC2+/- rats than in wild-type animals. Thus, the cognitive phenotype and, possibly, epilepsy in TSC patients may result not only from the focal hamartomatous lesions but also, from altered neuronal plasticity in the heterozygous tissue.

Alleles↗
PubMedDate not supplied

Measurement of dose distributions of linear energy transfer in matter irradiated by fast neutrons.

A detector has been developed and used to measure dose distributions versus linear energy transfer to thin gas targets in spherical geometry from fast neutron irradiation of tissue-equivalent plastic and carbon. The detector is a hemispherical proportional counter with a Cs(T1) scintillator at the center of the hemisphere. The coincidence of the proportional counter signals constrain the measurements to charged particles traversing the radius of the hemisphere. The charged particle energy deposition distributions are directly measured for a known pathlength. The A-150 kerma factor was measured at a neutron energy of 14.8 MeV and is in agreement with tabulated values. The carbon kerma factor measurements are less than the tabulated value at 14.8 MeV. The alpha-particle production in carbon was measured for neutron energies from 14.1 to 14.8 MeV and is compared with existing data.

Energy Transfer↗
PubMed2002

Evaluating geometric accuracy of multi-platform stereotactic neuroimaging in radiosurgery.

We used a spherical phantom to evaluate geometric accuracy in multi-platform stereotactic neuroimaging for radiosurgery. The phantom consisted of two plastic 16-cm-diameter hemispheres in which an exchangeable 8-cm plastic functional cube was incorporated. The functional cube contained cylinder and point targets. The targets were filled with a mixed aqueous solution of 2-mM copper sulfate and 300-mg/ml iodinated contrast medium and were visible on both MR and X-ray images. Two MR scanners and a biplane X-ray angio-suite were used to scan the phantom stereotactically in two sessions of the experiment. The angio-suite was equipped with digital subtraction and distortion-correction software. The resulting stereotactic images were transferred to a dose-planning computer for length measurement and coordinate determination of the targets. The mean errors of the measured cylinder length on distortion non-corrected X-ray stereotactic images were 0.24 +/- 0.14 and 0.73 +/- 0.10 mm, respectively, in the experiments; on distortion-corrected images 0.22 +/- 0.10 and 0.35 +/- 0.39 mm. They were 0.50 +/- 0.24, 0.25 +/- 0.19 and 0.49 +/- 0.34, 0.23 +/- 0.25 mm, respectively, of the two MR scanners. The mean errors of coordinate determination of point targets between the stereotactic MR and the distortion-corrected X-ray images were 0.70 +/- 0.18, 0.52 +/- 0.22 and 0.76 +/- 0.25, 0.40 +/- 0.10 mm, respectively, in the experiments. We found that the overall geometric errors of target delineation between stereotactic MR and X-ray images were in the submillimeter range. The current study validates the multi-platform and multi-facility stereotactic neuroimaging practice and ensures imaging accuracy in radiosurgery.

Angiography↗
PubMed2005

Calcineurin localization in skeletal muscle offers insights into potential new targets.

The Ca(2+)/calmodulin-activated protein phosphatase, calcineurin, is believed to regulate the development and function of skeletal and cardiac muscle. Striated muscle contains many calcineurin substrates, a few of which have been colocalized or found in molecular complexes with calcineurin. We examined the subcellular distribution of calcineurin in developing rat skeletal muscle cells and adult mouse skeletal muscle fibers by immunofluorescence microscopy. We found low levels of calcineurin immunoreactivity in the cytoplasm of myoblasts and higher levels in cytoplasmic vesicles of myotubes. Most of these vesicles were not immunoreactive for ryanodine receptors and, those that were, represented a small fraction of nascent triad junctions. In adult myofibers, calcineurin was largely associated with triads. Weaker calcineurin immunoreactivity occurred in the sarcoplasmic reticulum at the level of the M line. Unexpectedly, we found tiny clusters of calcineurin associated with nucleoli of developing myofiber nuclei. There were one to three clusters per nucleolus, either within or at the edges of fibrillar centers where ribosomal genes are transcribed. This suggests a role for calcineurin in regulating ribosome synthesis. Our findings suggest a variety of potential new targets and pathways through which calcineurin could regulate skeletal muscle development and plasticity and underscore the importance of spatial specificity in this regulation.

Animals↗
PubMed1998

Neurotrophins in the developing and regenerating visual system.

The neurotrophins NGF, BDNF, NT-3 and NT-4 have a wide range of effects in the development and regeneration of neural circuits in the visual system of vertebrates. This review focuses on the localization and functions of neurotrophins in the retina, lateral geniculate nucleus, suprachiasmatic nucleus, superior colliculus/optic tectum, and isthmic nuclei. Research of the past 20 years has shown that neurotrophins and their receptors are localized in numerous visual centers from the retina to the visual cortex, and that neurotrophins influence proliferation, neurite outgrowth and survival of cells in the visual system in vitro and in vivo. A relationship between electrical activity and neurotrophic functions has been established in several visual centers in the CNS, and neurotrophins have been implicated in synaptic plasticity in the visual cortex. Besides functions of neurotrophins as retrograde, target-derived trophic factors, recent data indicate that neurotrophins may have anterograde, afferent as well as local, paracrine actions in the retina, optic nerve and the visual cortex. Some neurotrophins appear to regulate proliferation and survival of glial cells in the optic pathways. Neurotrophins increase the survival of retinal ganglion cells after axotomy or ischemia and they promote the regeneration of retinal ganglion cell axons in some vertebration. Neurotrophins also rescue photoreceptors from degeneration. These findings implicate the neurotrophins not only as important regulators during development, but also as potential therapeutic agents in degenerative retinal diseases and after optic nerve injury.

Animals↗
PubMed2004

Calcium-calmodulin-dependent kinase II modulates Kv4.2 channel expression and upregulates neuronal A-type potassium currents.

Calcium-calmodulin-dependent kinase II (CaMKII) has a long history of involvement in synaptic plasticity, yet little focus has been given to potassium channels as CaMKII targets despite their importance in repolarizing EPSPs and action potentials and regulating neuronal membrane excitability. We now show that Kv4.2 acts as a substrate for CaMKII in vitro and have identified CaMKII phosphorylation sites as Ser438 and Ser459. To test whether CaMKII phosphorylation of Kv4.2 affects channel biophysics, we expressed wild-type or mutant Kv4.2 and the K(+) channel interacting protein, KChIP3, with or without a constitutively active form of CaMKII in Xenopus oocytes and measured the voltage dependence of activation and inactivation in each of these conditions. CaMKII phosphorylation had no effect on channel biophysical properties. However, we found that levels of Kv4.2 protein are increased with CaMKII phosphorylation in transfected COS cells, an effect attributable to direct channel phosphorylation based on site-directed mutagenesis studies. We also obtained corroborating physiological data showing increased surface A-type channel expression as revealed by increases in peak K(+) current amplitudes with CaMKII phosphorylation. Furthermore, endogenous A-currents in hippocampal pyramidal neurons were increased in amplitude after introduction of constitutively active CaMKII, which results in a decrease in neuronal excitability in response to current injections. Thus CaMKII can directly modulate neuronal excitability by increasing cell-surface expression of A-type K(+) channels.

Animals↗
PubMed2001

Physiological modulation of rabphilin phosphorylation.

The dynamic modulation of protein function by phosphorylation plays an important role in regulating synaptic plasticity. Several proteins involved in synaptic transmission have been shown to be targets of protein kinases and phosphatases. A thorough analysis of the physiological role of these modifications has been hampered by the lack of reagents that specifically recognize the phosphorylated states of these proteins. In this study we analyze the physiological modulation of rabphilin using phosphospecific antibodies. We show that phosphorylation on serine-234 and serine-274 of rabphilin is dynamically regulated both under basal and stimulated conditions by the activity of kinases and phosphatases. The two sites are differentially phosphorylated by the stimulation of various kinases, suggesting a possible convergence of different pathways to modulate the function of the protein. Maximal stimulation was observed under plasma membrane-depolarizing conditions that trigger synaptic vesicle exocytosis. The increase in phosphorylation was critically dependent on external Ca(2+) and on the presence of Rab3a, a small GTPase that recruits rabphilin to synaptic vesicles. The rapid phosphorylation and dephosphorylation during and after stimulation demonstrates the transient nature of the modification. Our results indicate that rabphilin is phosphorylated on synaptic vesicles by Ca(2+)-dependent kinases that become active in synaptic terminals during exocytosis. We have found that phosphorabphilin has a reduced affinity for membranes; we therefore propose that the modulation of the membrane association of rabphilin has a role in the synaptic vesicle life cycle, perhaps in vesicle mobilization in preparation for subsequent rounds of neurotransmission.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Regenerative events in the olivocerebellar pathway.

Mature neurons display a wide range of regenerative capabilities. As a general rule, peripheral neurons have the highest regenerative abilities both in the form of terminal sprouting and of axonal elongation following axotomy, regardless of the distance of the lesion from the cell body. In contrast, in central neurons reactive sprouting has been demonstrated in a limited number of neuronal populations and this type of growth may be dependent on the constitutive presence of specific growth-associated proteins. Central axon elongation is critically dependent on the presence of suitable environment and on the intrinsic capabilities of each neuronal population. These capabilities are controlled at least in part by repressive signals that are mainly located along the axons. They are more easily disclosed when a short axon stump is left after axotomy. The adult olivary neurons offer a unique model in the central nervous system for their remarkable plastic properties: i) they undergo extensive remodeling of their terminal arborizations following target manipulations or under the influence of electrical activity; ii) they are capable of axonal regeneration in a suitable environment; iii) their response to injury does not depend on the distance of the axotomy from the cell body. In this respect they are similar to peripheral neurons and likely their target cells are the main source of the repressive signals control-ling growth genes. The demonstration that this pathway is also able to find the proper target cells provides a striking example of how the mature brain may be repaired through appropriate manipulations.

Animals↗
PubMedDate not supplied

[The first experience in interstitial brachytherapy for primary and metastatic tumors of the brain].

In 2001-2002, the authors performed a course of brachytherapy in 15 patients with inoperable primary, recurrent, and metastatic brain tumors. The histostructural distribution was as follows: low-grade astrocytoma (grade II according to the WHO classification) in 2 patients, anaplastic astrocytoma (AA) in 3, glioblastoma multiforme (GBM) in 5. Five patients had solid tumor deposits in the brain. Computer tomographic (CT) and magnetic resonance imaging (MRI) data were used to define a path for forthcoming biopsy and implantation at a "Stryker" navigation station, by taking into account the anatomy of the brain, vessels, and functionally significant areas. After having histological findings, plastic intrastats whose number had been determined by the volume of a target were implanted into a tumor by the predetermined path. Dosimetric planning was accomplished by using CT and MRI images on an "Abacus" system. The final stage involved irradiation on a "GammaMed plus" with a source of 192Ir. Irradiation was given, by hyperfractionating its dose (3-4 Gy twice daily at an interval of 4-5 hours) to the total focal dose (TFD) of 36-44 Gy. Patients with gliomas untreated with radiation also underwent external radiation in a TFD of 54-56 Gy and patients with brain metastases received total external irradiation of the brain in a TFD of 36-40 Gy. The tolerance of a course of irradiation was fair. In patients with AA and GBM, one-year survival was observed in 66 and 60%, respectively; in those having metastasis, it was in 20%. Six patients died from progressive disease. All patients with low-grade astrocytoma and one patient with anaplastic astrocytoma were alive at month 24 after treatment termination. The mean lifespan of patients with malignant gliomas and solid tumor metastasis was 11.5 and 5.8 months, respectively. Brachytherapy is a noninvasive and tolerable mode of radiotherapy that increases survival in some groups of patients with inoperable brain tumors.

Adult↗
PubMed2000

Mice deficient in the polysialyltransferase ST8SiaIV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity.

Functional properties of the neural cell adhesion molecule (NCAM) are strongly influenced by polysialylation. We used gene-targeting to generate mice lacking ST8SiaIV/PST-1, one of the polysialyltransferases responsible for addition of polysialic acid (PSA) to NCAM. Mice homozygous for the null mutation reveal normal development of gross anatomical features. In contrast to NCAM-deficient mice, olfactory precursor cells in the rostral migratory stream express PSA and follow their normal pathway. Furthermore, delamination of mossy fibers in the hippocampal CA3 region, as found in NCAM-deficient mice, does not occur in ST8SiaIV mutants. However, during postnatal development these animals show a decrease of PSA in most brain regions compared to wild-type animals. Loss of PSA in the presence of NCAM protein but in the absence of obvious histological changes allowed us to directly address the role of PSA in synaptic plasticity. Schaffer collateral-CA1 synapses, which express PSA in wild types, showed impaired long-term potentiation (LTP) and long-term depression (LTD) in adult mutants. This impairment was age-dependent, following the time course of developmental disappearance of PSA. Contrary to NCAM mutant mice, LTP in ST8SiaIV mutants was undisturbed at mossy fiber-CA3 synapses, which do not express PSA in wild-type mice. The results demonstrate an essential role for ST8SiaIV in synaptic plasticity in hippocampal CA1 synapses, whereas PSA produced by different polysialyltransferase or polysialyltransferases at early stages of differentiation regulates migration of neural precursor cells and correct lamination of mossy fibers. We suggest that NCAM but not PSA is likely to be important for LTP in the hippocampal CA3 region.

Aging↗
PubMed2003

Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors.

Glutamate signalling plays key physiological roles in excitatory neurotransmission and CNS plasticity, but also mediates excitotoxicity, the process responsible for triggering neurodegeneration through glutamate receptor overactivation. Excitotoxicity is thought to be a key neurotoxic mechanism in neurological disorders, including brain ischemia, CNS trauma and epilepsy. However, treating excitotoxicity using glutamate receptor antagonists has not proven clinically viable, necessitating more sophisticated approaches. Increasing knowledge of the composition of the postsynaptic density at glutamatergic synapses has allowed us to extend our understanding of the molecular mechanisms of excitotoxicity and to dissect out the distinct signalling pathways responsible for excitotoxic damage. Key molecules in these pathways are physically linked to the cytoplasmic face of glutamate receptors by scaffolding proteins that exhibit binding specificity for some receptors over others. This imparts specificity to physiological and pathological glutamatergic signalling. Recently, we have capitalized on this knowledge and, using targeted peptides to selectively disrupt intracellular interactions linked to glutamate receptors, have blocked excitotoxic signalling in neurones. This therapeutic approach circumvents the negative consequences of blocking glutamate receptors, and may be a practical strategy for treating neurological disorders that involve excitotoxicity.

Animals↗
PubMed1977

Spontaneous, augmentable cell-mediated cytotoxicity with limited target cell specificity in human blood.

Nonadherent and nonphagocytic lymphoid cells from human peripheral blood became strongly cytotoxic against 51Cr-labeled chicken red blood cells and cells from an established human myeloma cell line when subjected to repeated cycles of washing in phosphate buffered saline or treated with trypsin or lecithinase. Prior to augmentation the effector cells pass nylon wool columns that remove practically all surface IgG-positive cells, but after augmentation they are retained in such columns. Augmentation does not make them phagocytic or adherent to plastic surfaces. Incubation at 37 degrees C of augmented cells prior to addition on the target cells restores the original nonaggressive state. Morphologically the cells making contact with the target cells are small or intermediate-sized mononuclear cells.

Animals↗
PubMed2005

An Aplysia type 4 phosphodiesterase homolog localizes at the presynaptic terminals of Aplysia neuron and regulates synaptic facilitation.

The cAMP-dependent signaling pathway is critically involved in memory-related synaptic plasticity. cAMP-specific type 4 phosphodiesterases (PDE4) play a role in this process by regulating the cAMP concentration. However, it is unclear how PDE4 is involved in regulating synaptic plasticity. To address this issue in Aplysia sensory-to-motor synapses, we identified a long isoform of the PDE4 homolog in Aplysia kurodai (apPDE), with genetic and biochemical properties similar to those of mammalian PDE4s. Furthermore, apPDE is localized to the membrane and presynaptic region. Both apPDE overexpression and knock-down impaired short- and long-term facilitation, indicating that an appropriate expression level of apPDE in synaptic regions is required for normal synaptic facilitation. By using fluorescence resonance energy transfer-based measurement of in vivo protein kinase A (PKA) activation, we found that the PKA activation by 5-hydroxytryptamine (5-HT) was impaired in both apPDE-overexpressed and knock-down synapses. Analogous to the inhibition of apPDE by RNA interference, chronic rolipram treatment before 5-HT stimulation also impaired the PKA activation by 5-HT, suggesting that regulation of the synaptic cAMP level by PDE4 is critical for normal synaptic facilitation. Together, we suggest that PDE4s localized in the synapses play a critical role in regulating the optimum cAMP level required for normal synaptic plasticity.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Immunologic control of a retrovirus-associated murine adenocarcinoma. VIII. Corynebacterium parvum-activated natural killer cells as potent antibody-dependent cell-mediated cytotoxicity effectors.

The antibody-dependent lytic activity of Corynebacterium parvum-induced peritoneal exudate cells was examined in vitro by utilizing AD755a tumor targets and a homologous anti-AD755a hyperimmune serum. Maximum antibody-dependent cell-mediated cytolysis (ADCC) of tumor targets was achieved within 4 hours of incubation. ADCC activity was found primarily in the plastic nonadherent cell population and was greatly enriched following removal of phagocytic cells by carbonyl iron. Phenotypically, the cells active in short-term ADCC were Qa-5+, ASGM-1+, Thy 1.2+, and NK 1.1+ and were unaffected by treatment with Lyt 1.2, Lyt 2.2, MAC-1, or I-Ab antibodies plus complement. Cells active in antibody-independent lysis of AD755a targets were phenotypically identical to antibody-dependent effectors. Although indicative of a natural killer (NK) cell phenotype, C. parvum-induced effectors differed from "spontaneous" splenic NK cells in their relative sensitivity to anti-Thy 1.2 as well as to anti-NK 1.1 treatment. Unlike the IgG2a-dependent lysis of AD755a-derived cells by inflammatory macrophages, all IgG isotypes of antiAD755a serum were equally effective in ADCC mediated by C. parvum NK cells. Finally, treatment of C. parvum-inoculated animals with anti-ASGM-1 serum eliminated in vitro NK activity and abrogated the in vivo therapeutic effects of hyperimmune serum. These findings, together with other correlations detailed herein, strongly suggested that C. parvum-activated NK cells appeared to represent a unique subset of NK cells that can serve as potent effectors in the antibody-dependent killing of AD755a tumor cells.

Adenocarcinoma↗