Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.12 (PKG)
 2,515 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of (+/-)cis-2-methylspilo(1,3-oxathiolane-5,3')quinuclidine (SNI-2011) on the secretory pathway of amylase in parotid tissues was investigated. SNI-2011-induced exocytosis was inhibited by a cell-permeable Ca(2+) chelator or inhibitors of calmodulin kinase II, neuronal nitric oxide synthase (nNOS), soluble guanyl cyclase, cyclic GMP-dependent protein kinase (PKG), and myosin light chain kinase, suggesting that these enzymes were coupled with the exocytosis. Stimulation with SNI-2011 of isolated rat parotid acinar cells loaded with 4,5-diaminofluorescein/diacetate (DAF-2/DA) induced a fast increase in DAF fluorescence corresponding to an increase in the NO production. SNI-2011-induced amylase secretion from parotid tissues in nNOS knockout mice has not been observed yet in spite of the expression of muscarinic M(3) receptors and the maintenance of secretory response to isoproterenol in the tissues. These results indicate the implication of the activation of Ca(2+)- and calmodulin-dependent enzymes and NOS-PKG signaling pathway in SNI-2011-induced amylase secretion from parotid acinar cells.
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PMID:Effect of SNI-2011 on amylase secretion from parotid tissue in rats and in neuronal nitric oxide synthase knockout mice. 1262 May 14

The induction of a long-term hyperexcitability (LTH) in vertebrate nociceptive sensory neurons (SNs) after nerve injury is an important contributor to neuropathic pain in humans, but the signaling cascades that induce this LTH have not been identified. In particular, it is not known how injuring an axon far from the cell soma elicits changes in gene expression in the nucleus that underlie LTH. The nociceptive SNs of Aplysia (ap) develop an LTH with electrophysiological properties after axotomy similar to those of mammalian neurons and are an experimentally useful model to examine these issues. We cloned an Aplysia PKG (cGMP-dependent protein kinase; protein kinase G) that is homologous to vertebrate type-I PKGs and found that apPKG is activated at the site of injury in the axon after peripheral nerve crush. The active apPKG is subsequently retrogradely transported to the somata of the SNs, but apPKG activity does not appear in other neurons whose axons are injured. In the soma, apPKG phosphorylates apMAPK (Aplysia mitogen-activated protein kinase), resulting in its entry into the nucleus. Surprisingly, studies using recombinant proteins in vivo and in vitro indicate that apPKG directly phosphorylates the threonine moiety in the T-E-Y activation site of apMAPK when the -Y- site contains a phosphate. We used inhibitors of nitric oxide synthase, soluble guanyl cyclase, or PKG after nerve injury, and found that each prevented the appearance of the LTH. Moreover, blocking apPKG activation prevented the nuclear import of apMAPK. Consequently, the nitric oxide-PKG-MAPK pathway is a potential target for treatment of neuropathic pain.
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PMID:A neuronal isoform of protein kinase G couples mitogen-activated protein kinase nuclear import to axotomy-induced long-term hyperexcitability in Aplysia sensory neurons. 1532 6

Nitric oxide (NO) is an intercellular retrograde messenger involved in several physiological processes such as synaptic plasticity, hippocampal long-term potentiation (LTP), and learning and memory. Moreover NO signaling is implicated in the pathophysiology of brain ischemia. In this study, we have characterized the role of NO/cGMP signaling cascade in the induction and maintenance of post-ischemic LTP (iLTP) in rat brain slices. Moreover, we have investigated the possible inhibitory action of zonisamide (ZNS) on this pathological form of synaptic plasticity as well as the effects of this antiepileptic drug (AED) on physiological activity-dependent LTP. Finally, we have characterized the possible interaction between ZNS and the NO/cGMP/PKG-dependent pathway involved in iLTP. Here, we provided the first evidence that an oxygen and glucose deprivation episode can induce, in CA1 hippocampal slices, iLTP by modulation of the NO/cGMP/PKG pathway. Additionally, we found that while ZNS application did not affect short-term synaptic plasticity and LTP induced by high-frequency stimulation, it significantly reduced iLTP. This reduction was mimicked by bath application of NO synthase inhibitors and a soluble guanyl cyclase inhibitor. The effect of ZNS was prevented by either the application of a NO donor or drugs increasing intracellular levels of cGMP and activating PKG. These findings are in line with the possible use of AEDs, such as ZNS, as a possible neuroprotective strategy in brain ischemia. Moreover, these findings strongly suggest that NO/cGMP/PKG intracellular cascade might represent a physiological target for neuroprotection in pathological forms of synaptic plasticity such as hippocampal iLTP.
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PMID:A critical role of NO/cGMP/PKG dependent pathway in hippocampal post-ischemic LTP: modulation by zonisamide. 2174 21

Photoreceptor cyclic nucleotide-gated (CNG) channels regulate Ca2+ influx in rod and cone photoreceptors. Mutations in cone CNG channel subunits CNGA3 and CNGB3 are associated with achromatopsia and cone dystrophies. Mice lacking functional cone CNG channel show endoplasmic reticulum (ER) stress-associated cone degeneration. The elevated cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase (PKG) signaling and upregulation of the ER Ca2+ channel ryanodine receptor 2 (RyR2) have been implicated in cone degeneration. This work investigates the potential contribution of RyR2 to cGMP/PKG signaling-induced ER stress and cone degeneration. We demonstrated that the expression and activity of RyR2 were highly regulated by cGMP/PKG signaling. Depletion of cGMP by deleting retinal guanylate cyclase 1 or inhibition of PKG using chemical inhibitors suppressed the upregulation of RyR2 in CNG channel deficiency. Depletion of cGMP or deletion of Ryr2 equivalently inhibited unfolded protein response/ER stress, activation of the CCAAT-enhancer-binding protein homologous protein, and activation of the cyclic adenosine monophosphate response element-binding protein, leading to early-onset cone protection. In addition, treatment with cGMP significantly enhanced Ryr2 expression in cultured photoreceptor-derived Weri-Rb1 cells. Findings from this work demonstrate the regulation of cGMP/PKG signaling on RyR2 in the retina and support the role of RyR2 upregulation in cGMP/PKG signaling-induced ER stress and photoreceptor degeneration.
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PMID:Potential contribution of ryanodine receptor 2 upregulation to cGMP/PKG signaling-induced cone degeneration in cyclic nucleotide-gated channel deficiency. 3217 7