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151.
The mechanism of ciliary stimulation by acetylcholine: roles of calcium, PKA, and PKG 总被引:8,自引:0,他引:8 下载免费PDF全文
Stimulation of ciliary cells through muscarinic receptors leads to a strong biphasic enhancement of ciliary beat frequency (CBF). The main goal of this work is to delineate the chain of molecular events that lead to the enhancement of CBF induced by acetylcholine (ACh). Here we show that the Ca(2+), cGMP, and cAMP signaling pathways are intimately interconnected in the process of cholinergic ciliary stimulation. ACh induces profound time-dependent increase in cGMP and cAMP concentrations mediated by the calcium-calmodulin complex. The initial strong CBF enhancement in response to ACh is mainly governed by PKG and elevated calcium. The second phase of CBF enhancement induced by ACh, a stable moderately elevated CBF, is mainly regulated by PKA in a Ca(2+)-independent manner. Inhibition of either guanylate cyclase or of PKG partially attenuates the response to ACh of [Ca(2+)](i), but completely abolishes the response of CBF. Inhibition of PKA moderately attenuates and significantly shortens the responses to ACh of both [Ca(2+)](i) and CBF. In addition, PKA facilitates the elevation in [Ca(2+)](i) and cGMP levels induced by ACh, whereas an unimpeded PKG activity is essential for CBF enhancement mediated by either Ca(2+) or PKA. 相似文献
152.
Role of the nitric oxide/cyclic GMP/Ca2+ signaling pathway in the pyrogenic effect of interleukin-1β
Interleukin-1β (IL-1β) has a wide spectrum of inflammatory, metabolic, haemopoietic, and immunological properties. Because
it produces fever when injected into animals and humans, it is considered an endogenous pyrogen. There is evidence to suggest
that Ca2+ plays a critical role in the central mechanisms of thermoregulation, and in the intracellular signaling pathways controlling
fever induced by IL-1β and other pyrogens. Data from different labs indicate that Ca2+ and Na+ determine the temperature set point in the posterior hypothalamus (PH) of various mammals and that changes in Ca2+ and PGE2 concentrations in the cerebrospinal fluid (CSF) of these animals are associated with IL-1β-induced fever. Antipyretic drugs
such as acetylsalicylic acid, dexamethasone, and lipocortin 5-(204–212) peptide counteract IL-1β-induced fever and abolish
changes in Ca2+ and PGE2 concentrations in CSF. In vitro studies have established that activation of the nitric oxide (NO)/cyclic GMP (cGMP) pathway
is part of the signaling cascade transducing Ca2+ mobilization in response to IL-1β and that the ryanodine (RY)- and inositol-(1,4,5)-trisphosphate (IP3)-sensitive pools are the main source of the mobilized Ca2+. It is concluded that the NO/cGMP/Ca2+ pathway is part of the signaling cascade subserving some of the multiple functions of IL-1β. 相似文献
153.
Soluble guanylyl cyclase (sGC) is the main receptor for nitric oxide (NO), and so mediates a wide range of effects (e.g. vasodilatation, platelet disaggregation and neural signalling) through the accumulation of cGMP and the engagement of various downstream targets, such as protein kinases and ion channels. Until recently, our understanding of sGC functioning has been derived exclusively from studies of the enzyme in tissue homogenates or in its purified form. Here, NO binds to the haem prosthetic group of sGC, triggering a conformational change and a large increase in catalytic activity. The potency (EC50) of NO appears to be about 100–200 nM. The rate of activation of sGC by NO is rapid (milliseconds) and, in the presence of excess substrate, cGMP is formed at a constant rate; on removal of NO, sGC deactivates slowly (seconds–minutes). Recent investigation of the way that sGC behaves in its natural environment, within cells, has revealed several key differences. For example, the enzyme exhibits a rapidly desensitizing profile of activity; the potency of NO is 45 nM for the minimally-desensitized enzyme but becomes higher with time; deactivation of sGC on removal of NO is 25-fold faster than the fastest estimate for purified sGC. Overall, within cells, sGC behaves in a way that is analogous to the way that classical neurotransmitter receptors operate. The properties of cellular sGC have important implications for the understanding of NO-cGMP signalling. For example, the dynamics of the enzyme means that fluctuations in the rate of NO formation, even on subsecond time scale, will result in closely synchronized sGC activity in neighbouring cells; desensitization of sGC provides an economical way of generating a cellular cGMP signal and, in concert with phosphodiesterases, provides the basis for cGMP signal diversity, allowing different targets (outputs) to be selected from a common input (NO). Thus, despite exhibiting only limited molecular heterogeneity, cellular sGC functions in a way that introduces speed, complexity, and versatility into NO-cGMP signalling pathways. 相似文献
154.
Genistein is often used as an inhibitor of tyrosine kinases. A less studied side effect of genistein is an inhibition of cyclic AMP-phosphodiesterase (cAMP-PDE) activity resulting in increased cAMP accumulation. The effect of genistein on intracellular cAMP-levels, basal and forskolin-induced, was studied in A549 human airway epithelial cells and compared with the unspecific PDE inhibitor, isobutylmethylxanthine (IBMX). It was shown that genistein (50 M) increased basal cAMP and potentiated forskolin-induced cAMP accumulation to the same extent as IBMX (100 M). Thus, the use of genistein in studies on signaling transductions may result in erroneous conclusions since increased cAMP may cause or contribute to the observed effects. 相似文献
155.
Clark CB McKnight NL Frangos JA 《Biochemical and biophysical research communications》2002,299(2):258-262
The endothelium is known to sense and respond to its physical environment, but the underlying mechanisms and early events of endothelial cell mechanotransduction are not well understood. The present study measured G protein activation by mechanical strain in human umbilical vein endothelial cells (HUVEC) directly by photoincorporation of a hydrolysis resistant, radiolabeled GTP analog. Ten percent uniaxial strain at a strain rate of 20% s(-1) over 1min activated a 38kDa Galpha subunit 167+/-17% relative to controls, while 2% cyclic strain failed to significantly activate the protein (117+/-19%). A single cycle of 10% strain at 20% s(-1) strain rate activated the Galpha subunit 152+/-25%, while activation at the same strain but lower strain rate (0.3% s(-1)) was not significantly different from controls (116+/-12%). Western blot analysis identified the 38kDa protein as Galpha(q/11). These results demonstrate the rapid activation of G proteins in HUVEC by cyclic uniaxial strain in a strain- and strain rate-dependent manner. 相似文献
156.
Stein O Ben-Naim M Dabach Y Hollander G Stein Y 《Biochemical and biophysical research communications》2002,290(5):1376-1381
Cholesterol efflux from peritoneal macrophages of mice C57BL/6 susceptible and C3H resistant to atherosclerosis was compared, using apoprotein A-I as acceptor. The elicited macrophages were labeled with 3H-cholesterol and cholesterol enriched by incubation for 24 h with acetylated LDL. After incubation for 6 or 24 h, 3H-cholesterol efflux to free apoA-I (10 microg/ml) was significantly higher with macrophages derived from C3H mice compared to C57BL/6 mice. The cells were also pretreated with 0.3-0.45 mM cyclic AMP, 10 microM 9-cis-retinoic acid or 10 microM 22(R)-hydroxycholesterol, RXR and LXR ligands. Treatment with cyclic AMP, RXR, or LXR ligands, resulted in enhancement of 3H-cholesterol efflux in both strains. Under all conditions, 3H-cholesterol efflux was significantly higher in C3H compared to C57BL/6 macrophages. In conclusion, the higher cholesterol efflux from C3H macrophages could contribute toward the resistance of this strain to diet-induced atherosclerosis despite hypercholesterolemia. 相似文献
157.
Short-term (2–30 min) cyclic stretch activates the Na pump in cultured aortic smooth muscle cells (ASMCs). This effect of
stretch involves the phosphotidylinositol 3-kinase (PI 3-kinase) participation. Presently, we investigated whether this stimulation
is the result of translocation of Na+,K+-ATPase from endosomes to the plasma membrane. ASMCs were stretched 20% for 5 min using the Flexercell Strain Unit. The plasma
membrane and endosome fractions were isolated and Western blotted to localize the Na+,K+-ATPase α-1-subunit protein. Membrane marker enzyme, 5′ nucleotidase activity, and the early and recycling endosome markers
Rab4 and Rab11 were used to verify the enrichment of these fractions. Stretch increased Na+,K+-ATPase α-1 expression in plasma membrane fractions and decreased it in endosomes. PI 3-kinase inhibitors LY294002 and wortmannin
blocked the stretch-induced translocation of the Na+,K+-ATPase α-1-subunit. Rab4 and Rab11 were enriched in the endosomal fraction, whereas 5′ nucleotidase activity was enriched
in the plasma membrane fraction. We conclude that stimulation of the Na pump activity by shortterm cyclic stretch is the result,
at least in part, of transport of the α-subunit of the enzyme from endosomes to the plasma membrane. 相似文献
158.
Regulation of neuronal proliferation and differentiation by nitric oxide 总被引:16,自引:0,他引:16
Gibbs SM 《Molecular neurobiology》2003,27(2):107-120
Many studies have revealed the free radical nitric oxide (NO) to be an important modulator of vascular and neuronal physiology.
It also plays a developmental role in regulating synapse formation and patterning. Recent studies suggest that NO may also
mediate the switch from proliferation to differentiation during neurogenesis. Many mechanisms of this response are conserved
between neuronal precursor cells and the cells of the vascular system, where NO can inhibit the proliferative response of
endothelial and smooth-muscle cells to injury. In cultured neuroblastoma cells, NO synthase (NOS) expression is increased
in the presence of various growth factors and mitogens. Subsequent production of NO leads to cessation of cell division and
the acquisition of a differentiated phenotype. The inhibitory action of NO on neuroblast proliferation has also been demonstrated
in vivo for vertebrate and invertebrate nervous systems, as well as in the adult brain. Potential downstream effectors of
NO include the second messenger cyclic GMP, activation of the tumor-suppressor genes p53 and Rb, and the cyclin-dependent kinase inhibitor p21. These studies highlight a new role for NO in the nervous system, as a coordinator of proliferation and patterning during
neural development and adult neurogenesis. 相似文献
159.
Orstavik S Eide T Collas P Han IO Taskén K Kieff E Jahnsen T Skålhegg BS 《Biology of the cell / under the auspices of the European Cell Biology Organization》2000,92(1):27-37
Previously, we have identified and characterized nuclear AKAP95 from man which targets cyclic AMP (cAMP)-dependent protein kinase (PKA)-type II to the condensed chromatin/spindle region at mitosis. Here we report the cloning of a novel nuclear protein with an apparent molecular mass of 95 kDa that is similar to AKAP95 and is designated HA95 (homologous to AKAP95). HA95 cDNA sequence encodes a protein of 646 amino acids that shows 61% homology to the deduced amino acid sequence of AKAP95. The HA95 gene is located on chromosome 19p13.1 immediately upstream of the AKAP95 gene. Both HA95 and AKAP95 genes contain 14 exons encoding similar regions of the respective proteins, indicating a previous gene duplication event as the origin of the two tandem genes. Despite their apparent similarity, HA95 does not bind RII in vitro. HA95 contains a putative nuclear localization signal in its N-terminal domain. It is localized exclusively into the nucleus as demonstrated in cells transfected with HA95 fused to either green fluorescence protein or the c-myc epitope. In the nucleus, the HA95 protein is found as complexes directly associated with each other or indirectly associated via other nuclear proteins. In interphase, HA95 is co-localized with AKAP95, but the two proteins are not biochemically associated. At metaphase, both proteins co-localize with condensed chromosomes. The similarity in sequence and localization of HA95 and AKAP95 suggests that the two molecules constitute a novel family of nuclear proteins that may exhibit related functions. 相似文献
160.
Nicotinic acid adenine dinucleotide phosphate (NAADP(+)) is an essential regulator of T-lymphocyte Ca(2+)-signaling 总被引:2,自引:0,他引:2
Microinjection of human Jurkat T-lymphocytes with nicotinic acid adenine dinucleotide phosphate (NAADP(+)) dose-dependently stimulated intracellular Ca(2+)-signaling. At a concentration of 10 nM NAADP(+) evoked repetitive and long-lasting Ca(2+)-oscillations of low amplitude, whereas at 50 and 100 nM, a rapid and high initial Ca(2+)-peak followed by trains of smaller Ca(2+)-oscillations was observed. Higher concentrations of NAADP(+) (1 and 10 microM) gradually reduced the initial Ca(2+)-peak, and a complete self-inactivation of Ca(2+)-signals was seen at 100 microM. The effect of NAADP(+) was specific as it was not observed with nicotinamide adenine dinucleotide phosphate. Both inositol 1,4, 5-trisphosphate- and cyclic adenosine diphosphoribose-mediated Ca(2+)-signaling were efficiently inhibited by coinjection of a self-inactivating concentration of NAADP(+). Most importantly, microinjection of a self-inactivating concentration of NAADP(+) completely abolished subsequent stimulation of Ca(2+)-signaling via the T cell receptor/CD3 complex, indicating that a functional NAADP(+) Ca(2+)-release system is essential for T-lymphocyte Ca(2+)-signaling. 相似文献