Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SD rats were pretreated with whole body hyperthermia (rectal 42 degrees C) for 15 min. The level of calcitonin gene-related peptide (CGRP) in plasma, and alpha- and beta-CGRP mRNA as well as heme oxygenease-1 and heme oxygenase-2 mRNA in dorsal root ganglia were determined by radioimmunoassay and semi-quantitative reverse-transcription polymerase chain reaction, respectively. Heat stress induced only the expression of alpha-CGRP or heme oxygenease-1 but not beta-CGRP or heme oxygenase-2 mRNA, and the release of CGRP and induction of alpha-CGRP mRNA expression were abolished by pretreatment with Zinc protoporphyrin IX, the heme oxygenase inhibitor, or methylene blue, the inhibitor of soluble guanylate cyclase. These results indicate that induction of alpha-CGRP mRNA expression in rat DRG by heat stress involves the heme oxygenase-1/carbon monoxide pathway.
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PMID:Induction of alpha-calcitonin gene-related peptide mRNA expression in rat dorsal root ganglia by heat stress involves the heme oxygenase-1/carbon monoxide pathway. 1203 Aug 15

cGMP signaling elicited by activation of the transmembrane receptor guanylyl cyclase Npr2 (also known as guanylyl cyclase B) by the ligand CNP controls sensory axon bifurcation of DRG and cranial sensory ganglion (CSG) neurons entering the spinal cord or hindbrain, respectively. Previous studies have shown that Npr2 is phosphorylated on serine and threonine residues in its kinase homology domain (KHD). However, it is unknown whether phosphorylation of Npr2 is essential for axon bifurcation. Here, we generated a knock-in mouse line in which the seven regulatory serine and threonine residues in the KHD of Npr2 were substituted by alanine (Npr2-7A), resulting in a nonphosphorylatable enzyme. Real-time imaging of cGMP in DRG neurons with a genetically encoded fluorescent cGMP sensor or biochemical analysis of guanylyl cyclase activity in brain or lung tissue revealed the absence of CNP-induced cGMP generation in the Npr27A/7A mutant. Consequently, bifurcation of axons, but not collateral formation, from DRG or CSG in this mouse mutant was perturbed at embryonic and mature stages. In contrast, axon branching was normal in a mouse mutant in which constitutive phosphorylation of Npr2 is mimicked by a replacement of all of the seven serine and threonine sites by glutamic acid (Npr2-7E). Furthermore, we demonstrate that the Npr27A/7A mutation causes dwarfism as described for global Npr2 mutants. In conclusion, our in vivo studies provide strong evidence that phosphorylation of the seven serine and threonine residues in the KHD of Npr2 is an important regulatory element of Npr2-mediated cGMP signaling which affects physiological processes, such as axon bifurcation and bone growth.SIGNIFICANCE STATEMENT The branching of axons is a morphological hallmark of virtually all neurons. It allows an individual neuron to innervate different targets and to communicate with neurons located in different regions of the nervous system. The natriuretic peptide receptor 2 (Npr2), a transmembrane guanylyl cyclase, is essential for the initiation of bifurcation of sensory axons when entering the spinal cord or the hindbrain. By using two genetically engineered mouse lines, we show that phosphorylation of specific serine and threonine residues in juxtamembrane regions of Npr2 are required for its enzymatic activity and for axon bifurcation. These investigations might help to understand the regulation of Npr2 and its integration in intracellular signaling systems.
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PMID:Regulation of the Natriuretic Peptide Receptor 2 (Npr2) by Phosphorylation of Juxtamembrane Serine and Threonine Residues Is Essential for Bifurcation of Sensory Axons. 3024 93

Endometriosis, an estrogen-dependent chronic inflammatory disease, is the most common cause of chronic pelvic pain. Here, we investigated the effects of linaclotide, a Food and Drug Administration-approved treatment for IBS-C, in a rat model of endometriosis. Eight weeks after endometrium transplantation into the intestinal mesentery, rats developed endometrial lesions as well as vaginal hyperalgesia to distension and decreased mechanical hind paw withdrawal thresholds. Daily oral administration of linaclotide, a peripherally restricted guanylate cyclase-C (GC-C) agonist peptide acting locally within the gastrointestinal tract, increased pain thresholds to vaginal distension and mechanical hind paw withdrawal thresholds relative to vehicle treatment. Furthermore, using a cross-over design, administering linaclotide to rats previously administered vehicle resulted in increased hind paw withdrawal thresholds, whereas replacing linaclotide with vehicle treatment decreased hind paw withdrawal thresholds. Retrograde tracing of sensory afferent nerves from the ileum, colon, and vagina revealed that central terminals of these afferents lie in close apposition to one another within the dorsal horn of the spinal cord. We also identified dichotomizing dual-labelled ileal/colon innervating afferents as well as colon/vaginal dual-labelled neurons and a rare population of triple traced ileal/colon/vaginal neurons within thoracolumbar DRG. These observations provide potential sources of cross-organ interaction at the level of the DRG and spinal cord. GC-C expression is absent in the vagina and endometrial cysts suggesting that the actions of linaclotide are shared through nerve pathways between these organs. In summary, linaclotide may offer a novel therapeutic option not only for treatment of chronic endometriosis-associated pain, but also for concurrent treatment of comorbid chronic pelvic pain syndromes.
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PMID:Linaclotide treatment reduces endometriosis-associated vaginal hyperalgesia and mechanical allodynia through viscerovisceral cross-talk. 3133 50