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 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurotrophins and semaphorin 3A are present along pathways and in targets of developing axons of dorsal root ganglion (DRG) sensory neurons. Growth cones of sensory axons are probably regulated by interaction of cytoplasmic signaling triggered coincidentally by both types of guidance molecules. We investigated the in vitro interactions of neurotrophins and semaphorin 3A (Sema3A) in modulating growth cone behaviors of axons extended from DRGs of embryonic day 7 chick embryos. Growth cones of DRGs raised in media containing 10(-9) m NGF or BDNF were more resistant to Sema3A-induced growth cone collapse than when DRGs were raised in 10(-11) m NGF. After overnight culture in 10(-11) m NGF, a 1 hr treatment with 10(-9) m NGF or BDNF was sufficient to increase growth cone resistance to Sema3A-induced collapse. This neurotrophin-mediated decrease in the collapse response of DRG growth cones was not associated with reduced expression on growth cones of the Sema3A-binding protein neuropilin-1. A series of pharmacological studies followed. Phosphatidylinositol 3 kinase activity is not required for these effects of NGF. The effects of inhibitors and activators of protein kinase A (PKA) indicate that PKA activity is involved in NGF modulation of Sema3A-induced growth cone collapse. The effects of inhibitors and activators of PKG indicate that PKG activity is involved in Sema3A-induced growth cone collapse. The effects of inhibitors also indicate that Rho-kinase activity is involved in Sema3A-induced growth cone collapse. These results are consistent with the idea that growth cone responses to an individual guidance cue depend on coincident signaling by other guidance cues and by other regulatory pathways.
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PMID:Nerve growth factor and semaphorin 3A signaling pathways interact in regulating sensory neuronal growth cone motility. 1215 45

Previous in vitro studies using cGMP or cAMP revealed a cross-talk between signaling mechanisms activated by axonal guidance receptors. However, the molecular elements modulated by cyclic nucleotides in growth cones are not well understood. cGMP is a second messenger with several distinct targets including cGMP-dependent protein kinase I (cGKI). Our studies indicated that the alpha isoform of cGKI is predominantly expressed by sensory axons during developmental stages, whereas most spinal cord neurons are negative for cGKI. Analysis of the trajectories of axons within the spinal cord showed a longitudinal guidance defect of sensory axons within the developing dorsal root entry zone in the absence of cGKI. Consequently, in cGKI-deficient mice, fewer axons grow within the dorsal funiculus of the spinal cord, and lamina-specific innervation, especially by nociceptive sensory neurons, is strongly reduced as deduced from anti-trkA staining. These axon guidance defects in cGKI-deficient mice lead to a substantial impairment in nociceptive flexion reflexes, shown using electrophysiology. In vitro studies revealed that activation of cGKI in embryonic dorsal root ganglia counteracts semaphorin 3A-induced growth cone collapse. Our studies therefore reveal that cGMP signaling is important for axonal growth in vivo and in vitro.
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PMID:cGMP-mediated signaling via cGKIalpha is required for the guidance and connectivity of sensory axons. 1241 79

Nerve growth factor (NGF) and semaphorin3A (Sema3A) are guidance cues found in pathways and targets of developing dorsal root ganglia (DRG) neurons. DRG growth cone motility is regulated by cytoplasmic signaling triggered by these molecules. We investigated interactions of NGF and Sema3A in modulating growth cone behaviors of axons extended from E7 chick embryo DRGs. Axons extending in collagen matrices were repelled by Sema3A released from transfected HEK293 cells. However, if an NGF-coated bead was placed adjacent to Sema3A-producing cells, axons converged at the NGF bead. Growth cones of DRGs raised in 10(-9) M NGF were more resistant to Sema3A-induced collapse than when DRGs were raised in 10(-11) M NGF. After overnight culture in 10(-11) M NGF, 1-hr treatment with 10(-9) M NGF also increased growth cone resistance to Sema3A. Pharmacological studies indicated that the activities of ROCK and PKG participate in the cytoskeletal alterations that lead to Sema3A-induced growth cone collapse, whereas PKA activity is required for NGF-mediated reduction of Sema3A-induced growth cone collapse. These results support the idea that growth cone responses to a guidance cue can be modulated by interactions involving coincident signaling by other guidance cues.
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PMID:Growth cones integrate signaling from multiple guidance cues. 1264 22

Licorice root is used to treat asthma as a component of Shaoyao-Gancao-tang, a traditional Chinese medicine formula. In this study, we investigated the tracheal relaxation effects of isoliquiritigenin, a flavonoid isolated from the roots of Glycyrrhiza glabra (a kind of Licorice), on guinea-pig tracheal smooth muscle in vitro and in vivo. The tension changes of isolated tracheal rings were isometrically recorded on a polygraph. The large-conductance Ca2+-activated K+ channels (BKCa) were measured by inside-out patch-clamp techniques and intracellular Ca2+concentrations ([Ca2+]i) were tested by microfluorometric method in guinea-pig tracheal smooth muscle cells (TSMCs). Isoliquiritigenin produced concentration-dependent relaxation in isolated guinea-pig tracheal rings precontracted with acetylcholine, KCl, and histamine. Pretreatments with charybdotoxin, ODQ and KT5823 attenuated the relaxation induced by isoliquiritigenin. Isoliquiritigenin significantly increased intracellular cGMP level in cultured TSMCs and inhibited the activity of phosphodiesterase (PDE) 5 in human platelets. Moreover, isoliquiritigenin increased by 9-fold the probability of BKCa channel openings of TSMCs in inside-out patches and markedly reduced [Ca2+]i rise induced by acetylcholine inTSMCs, pretreatment with KT5823 attenuated above two responses to isoliquiritigenin. In vivo experiment isoliquiritigenin significantly prolonged the latency time of histamine-acetylcholine aerosol-induced collapse and inhibited the increase of lung overflow induced by intravenously administered histamine dose-dependently. These data indicate that isoliquiritigenin relaxes guinea-pig trachea through a multiple of intracellular actions, including sGC activation, inhibition of PDEs, and associated activation of the cGMP/PKG signaling cascade, leading to the opening of BKCa channels and [Ca2+]i decrease through PKG-dependent mechanism and thus to tracheal relaxation.
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PMID:Isoliquiritigenin, a flavonoid from licorice, relaxes guinea-pig tracheal smooth muscle in vitro and in vivo: role of cGMP/PKG pathway. 1846 16

The Eph family tyrosine kinase receptors and their ligands, ephrins, play key roles in a wide variety of physiological and pathological processes including tissue patterning, angiogenesis, bone development, carcinogenesis, axon guidance, and neural plasticity. However, the signaling mechanisms underlying these diverse functions of Eph receptors have not been well understood. In this study, effects of Eph receptor activation on several important signal transduction pathways are examined. In addition, the roles of these pathways in ephrin-A5-induced growth cone collapse were assessed with a combination of biochemical analyses, pharmacological inhibition, and overexpression of dominant-negative and constitutively active mutants. These analyses showed that ephrin-A5 inhibits Erk activity but activates c-Jun N-terminal kinase. However, regulation of these two pathways is not required for ephrin-A5-induced growth cone collapse in hippocampal neurons. Artificial Erk activation by expression of constitutively active Mek1 and B-Raf failed to block ephrin-A5 effects on growth cones, and inhibitors of the Erk pathway also failed to inhibit collapse by ephrin-A5. Inhibition of JNK had no effects on ephrin-A5-induced growth cone collapse either. In addition, inhibitors to PKA and PI3-K showed no effects on ephrin-A5-induced growth cone collapse. However, pharmacological blockade of phosphotyrosine phosphatase activity, the Src family kinases, cGMP-dependent protein kinase, and myosin light chain kinase significantly inhibited ephrin-A5-induced growth cone collapse. These observations indicate that only a subset of signal transduction pathways is required for ephrin-A5-induced growth cone collapse.
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PMID:A subset of signal transduction pathways is required for hippocampal growth cone collapse induced by ephrin-A5. 1856

The cGMP-dependent protein kinase type I (cGKI) has multiple functions including a role in axonal growth and pathfinding of sensory neurons, and counteracts Semaphorin 3A (Sema3A)-induced growth cone collapse. Within the nervous system, however, the transcriptional regulation of cGKI is still obscure. Recently, the transcription factor and tumor suppressor p53 has been reported to promote neurite outgrowth by regulating the gene expression of factors that promote growth cone extension, but specific p53 targets genes that may counteract growth cone collapse have not been identified so far. Here, we show that p53 promotes cGKI expression in neuronal-like PC-12 cells and primary neurons by occupying specific regulatory elements in a chromatin environment during neuronal maturation. Importantly, we demonstrate that p53-dependent expression of cGKI is required for the ability of cGMP to counteract growth cone collapse. Growth cone retraction mediated by Sema3A is overcome by cGMP only in wild-type, but not in p53-null dorsal root ganglia. Reconstitution of p53 levels is sufficient to recover both cGKI expression and the ability of cGMP to counteract growth cone collapse, while cGKI overexpression rescues growth cone collapse in p53-null primary neurons. In conclusion, this study identifies p53 as a transcription factor that regulates the expression of cGKI during neuronal maturation and cGMP-dependent inhibition of growth cone collapse.
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PMID:The tumor suppressor p53 transcriptionally regulates cGKI expression during neuronal maturation and is required for cGMP-dependent growth cone collapse. 1995 67