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)

Crustacean molt-inhibiting hormone (MIH), a polypeptide produced by neurosecretory cells in eyestalk ganglia, suppresses the synthesis of ecdysteroid molting hormones by paired Y-organs. Data from several sources indicate the effects of MIH are mediated, at least in part, by a cGMP second messenger. Based on these and related findings, our working hypothesis is that the MIH receptor is a receptor guanylyl cyclase (rGC). In studies reported here, we used a PCR-based cloning strategy (RT-PCR followed by 5'- and 3'-RACE) to clone from blue crab (Callinectes sapidus) Y-organs a cDNA (CsGC-YO1) encoding a putative rGC. DNA sequence analysis revealed a 3807 base pair open reading frame encoding a 56 residue signal peptide and a 1213 residue rGC. Analysis of the deduced amino acid sequence showed that CsGC-YO1 contains the signature domains characteristic of rGCs, including an extracellular ligand-binding domain, a single transmembrane domain, a kinase-like domain, a dimerization domain, and a cyclase catalytic domain. CsGC-YO1 is most closely related to an rGC from the crayfish, Procambarus claikii (PcGC-M2, 58.4% identity), and rGCs from three insect species (33.1-37.5% identity). Conserved cysteine residues are similarly distributed in the extracellular domains of CsGC-YO1, PcGC-M2, and the three insect rGCs. RT-PCR revealed the CsGC-YO1 transcript is expressed in Y-organs and several other tissues. While other interpretations of the data are possible, our working hypothesis is that the cloned cDNA encodes an MIH receptor.
Gen Comp Endocrinol 2006 May 01
PMID:Molecular cloning of a putative receptor guanylyl cyclase from Y-organs of the blue crab, Callinectes sapidus. 1642 8

Cyclic nucleotide-gated (CNG) channels are a family of ion channels activated by the binding of cyclic nucleotides. Endogenous channels have been used to measure cyclic nucleotide signals in photoreceptor outer segments and olfactory cilia for decades. Here we have investigated the subcellular localization of cGMP signals by monitoring CNG channel activity in response to agonists that activate either particulate or soluble guanylyl cyclase. CNG channels were heterologously expressed in either human embryonic kidney (HEK)-293 cells that stably overexpress a particulate guanylyl cyclase (HEK-NPRA cells), or cultured vascular smooth muscle cells (VSMCs). Atrial natriuretic peptide (ANP) was used to activate the particulate guanylyl cyclase and the nitric oxide donor S-nitroso-n-acetylpenicillamine (SNAP) was used to activate the soluble guanylyl cyclase. CNG channel activity was monitored by measuring Ca2+ or Mn2+ influx through the channels using the fluorescent dye, fura-2. We found that in HEK-NPRA cells, ANP-induced increases in cGMP levels activated CNG channels in a dose-dependent manner (0.05-10 nM), whereas SNAP (0.01-100 microM) induced increases in cGMP levels triggered little or no activation of CNG channels (P < 0.01). After pretreatment with 100 microM 3-isobutyl-1-methylxanthine (IBMX), a nonspecific phosphodiesterase inhibitor, ANP-induced Mn2+ influx through CNG channels was significantly enhanced, while SNAP-induced Mn2+ influx remained small. In contrast, we found that in the presence of IBMX, both 1 nM ANP and 100 microM SNAP triggered similar increases in total cGMP levels. We next sought to determine if cGMP signals are compartmentalized in VSMCs, which endogenously express particulate and soluble guanylyl cyclase. We found that 10 nM ANP induced activation of CNG channels more readily than 100 muM SNAP; whereas 100 microM SNAP triggered higher levels of total cellular cGMP accumulation. These results suggest that cGMP signals are spatially segregated within cells, and that the functional compartmentalization of cGMP signals may underlie the unique actions of ANP and nitric oxide.
J Gen Physiol 2006 Jul
PMID:Natriuretic peptides and nitric oxide stimulate cGMP synthesis in different cellular compartments. 1676 93

Our ability to see in bright light depends critically on the rapid rate at which cone photoreceptors detect and adapt to changes in illumination. This is achieved, in part, by their rapid response termination. In this study, we investigate the hypothesis that this rapid termination of the response in red cones is dependent on interactions between the 9-methyl group of retinal and red cone opsin, which are required for timely metarhodopsin (Meta) II decay. We used single-cell electrical recordings of flash responses to assess the kinetics of response termination and to calculate guanylyl cyclase (GC) rates in salamander red cones containing native visual pigment as well as visual pigment regenerated with 11-cis 9-demethyl retinal, an analogue of retinal in which the 9-methyl group is missing. After exposure to bright light that photoactivated more than approximately 0.2% of the pigment, red cones containing the analogue pigment had a slower recovery of both flash response amplitudes and GC rates (up to 10 times slower at high bleaches) than red cones containing 11-cis retinal. This finding is consistent with previously published biochemical data demonstrating that red cone opsin regenerated in vitro with 11-cis 9-demethyl retinal exhibited prolonged activation as a result of slowed Meta II decay. Our results suggest that two different mechanisms regulate the recovery of responsiveness in red cones after exposure to light. We propose a model in which the response recovery in red cones can be regulated (particularly at high light intensities) by the Meta II decay rate if that rate has been inhibited. In red cones, the interaction of the 9-methyl group of retinal with opsin promotes efficient Meta II decay and, thus, the rapid rate of recovery.
J Gen Physiol 2006 Dec
PMID:Turning cones off: the role of the 9-methyl group of retinal in red cones. 1710 18

C-type natriuretic peptide (CNP) cDNA was cloned from the tilapia brain and its inferred mature sequence was chemically synthesized together with previously cloned tilapia A-type and B-type natriuretic peptides (ANP and BNP). The cloned CNP belongs to the CNP-1 type of teleosts. Reverse-transcription polymerase chain reaction showed that the ANP and BNP genes were hardly expressed in the tilapia brain and pituitary, whereas the CNP gene was expressed strongly in the brain and slightly in the pituitary. Effects of homologous natriuretic peptides (100 nM each) on growth hormone (GH) and prolactin (PRL) release were examined using dispersed tilapia pituitary cells. Tilapia ANP and BNP stimulated GH and PRL release during 4-8, and 8-24 h of incubation. BNP appeared to be more potent than ANP, also stimulating GH and PRL release during 0-4 h of incubation. CNP stimulated GH release only during 4-8 h of incubation; CNP was without effect on PRL release. All three NPs stimulated GH and PRL mRNA expression in dispersed pituitary cells following 24 h of incubation. ANP and BNP significantly elevated intracellular cGMP accumulation in dispersed pituitary cells after 15 min of exposure, whereas no effect of CNP was observed. These results indicate a long-lasting stimulation of GH and PRL release by ANP and BNP that is mediated, at least in part, by the guanylyl cyclase-linked NP receptor.
Gen Comp Endocrinol 2007 Jan 15
PMID:In vitro effects of homologous natriuretic peptides on growth hormone and prolactin release in the tilapia, Oreochromis mossambicus. 1710 75

The role of C-type natriuretic peptide (CNP) in the gastrointestinal tract is still unclear. This study was designed to investigate the effect of CNP on barium current (I(Ba)) through the L-type calcium channel in gastric antral myocytes of guinea pigs. The whole-cell patch clamp technique was performed in gastric antral myocytes isolated by collagenase in guinea pigs. CNP significantly inhibited I(Ba) in a dose-dependent manner at the concentrations of 0.001, 0.01, and 0.1 micromol/l, CNP inhibited I(Ba) to 81.56 +/- 2.48 %, 73.64 +/- 3.65 %, and 57.77 +/- 4.93 % of control at 0 mV, respectively. The values of steady-state half-inactivation voltage (33.6 +/- 2.6 mV and 33.8 +/- 3.4 mV, in control and CNP groups, respectively) or the half-activation voltage (-12.6 +/- 2.2 mV and 12.4 +/- 1.8 mV) of I(Ba) were not significantly changed (p > 0.05, n = 6). 8-br-cGMP (1 mmol/l) mimicked the effect of CNP on I(Ba), and the peak current of I(Ba) was inhibited from -403.84 +/- 61.87 pA to 318.94 +/- 67.17 pA (p < 0.05, n = 5). In the presence of LY83583 (0.1 micromol/l), a nonspecific inhibitor of guanylate cyclase, CNP (0.1 micromol/l)-induced inhibition of I(Ba) was partially blocked (n = 13, p < 0.05 ). However, when the cell was pretreated with zaprinast (0.1 micromol/l), an inhibitor of cyclic guanosine monophosphate (cGMP) sensitive phosphoesterase, the inhibitory effect of CNP on I(Ba) was significantly potentiated (n = 11, p < 0.05). KT5823 (1 micromol/l), a cGMP-dependent protein kinase (PKG) inhibitor, almost completely blocked CNP-induced inhibition of I(Ba). The results suggested that CNP can inhibit L-type calcium channel currents, and the inhibitory effect is mediated by pGC-cGMP-PKG-dependent signal pathway in gastric antral myocytes of guinea pigs.
Gen Physiol Biophys 2006 Dec
PMID:Inhibitory effect of C-type natriuretic peptide on L-type calcium channel currents in gastric antral myocytes of guinea pigs. 1735 30

Guanylin and uroguanylin are principal intestinal hormones secreted into the lumen to regulate ion and water absorption via a specific receptor, guanylyl cyclase-C (GC-C). As the intestine is an essential organ for seawater (SW) adaptation in teleost fishes, the intestinal guanylin system may play a critical role in SW adaptation. Molecular biological studies identified multiple guanylins (guanylin, uroguanylin and renoguanylin) and their receptors (GC-C1 and GC-C2) in eels. The relative potency of the three ligands on cGMP production in transiently expressed receptors was uroguanylin > guanylin >or= renoguanylin for CG-C1 and guanylin >or= renoguanylin > uroguanylin for GC-C2. Eel guanylin and GC-C genes are expressed exclusively in the intestine and kidney, and the level of expression is greater in SW eels than in freshwater (FW) eels except for renoguanylin. Physiological studies using Ussing chambers showed that the middle and posterior intestine are major sites of action of guanylins, where they act on the mucosal side to decrease short circuit current (I(sc)) in a dose-dependent manner. The ID(50) of guanylins for transport inhibition was 50-fold greater than that of atrial natriuretic peptide that acts from the serosal side as an endocrine hormone. However, only guanylins reversed I(sc) to levels below zero. Pharmacological analyses using various blockers showed that among transporters and channels localized on the intestinal cells of SW teleost fish, the cystic fibrosis transmembrane conductance regulator Cl(-) channel (CFTR) on the apical membrane is the major target of guanylins. Collectively, guanylins are synthesized locally in the intestine and secreted into the lumen to act on the GC-Cs in the apical membrane of eel intestinal cells. Then, intracellular cGMP production after ligand-receptor interaction activates CFTR and probably induces Cl(-) and/or HCO3- secretion into the lumen as suggested in mammals. The physiological significance of the anion secretion induced by the luminal guanylin/GC-C system on SW adaptation may rival or exceed that of the serosally derived natriuretic peptides in the euryhaline eel.
Gen Comp Endocrinol
PMID:The intestinal guanylin system and seawater adaptation in eels. 1756 Oct 18

Crustacean Y-organs synthesize ecdysteroid molting hormones. Synthesis of ecdysteroids by Y-organs is negatively regulated by a polypeptide neurohormone, molt-inhibiting hormone (MIH). Our laboratory has recently cloned from Y-organs of the blue crab (Callinectes sapidus) a cDNA (CsGC-YO1) encoding a putative receptor guanylyl cyclase (CsGC-YO1). We hypothesize that CsGC-YO1 is an MIH receptor. In studies reported here, antipeptide antibodies (anti-CsGC-YO1) were raised against a fragment of the extracellular domain of CsGC-YO1. Western blots showed affinity purified anti-CsGC-YO1 bound to the heterologously expressed extracellular domain, and to a protein in Y-organs that corresponded in size to the theoretical molecular mass of CsGC-YO1. Immunocytochemical studies with anti-CsGC-YO1 as primary antibody, showed CsGC-YO1 immunoreactivity was restricted to the peripheral margins of cells, and was not present in cytoplasm or nuclei. The results strongly suggest that CsGC-YO1 is a membrane-associated protein. Preincubation of Y-organs with anti-CsCG-YO1 blunted MIH-induced suppression of ecdysteroidogenesis. This finding represents the first demonstration of a link between CsGC-YO1 and MIH action. A real-time PCR assay for quantifying CsCG-YO1 was developed and validated. The assay was used to determine the abundance of the CsCG-YO1 transcript in Y-organs during a molt cycle: the level of CsGC-YO1 in Y-organs was elevated during intermolt (C(4)) and lower during premolt stages D(1)-D(3). The data suggest that the biological action of CsGC-YO1 in Y-organs is likely to be most pronounced during intermolt. The combined results are consistent with the hypothesis that CsGC-YO1 is an MIH receptor.
Gen Comp Endocrinol 2008 Feb 01
PMID:Studies of a receptor guanylyl cyclase cloned from Y-organs of the blue crab (Callinectes sapidus), and its possible functional link to ecdysteroidogenesis. 1809 88

The natriuretic peptide (NP) family is a seemingly ubiquitous sodium and volume reducing endocrine system of predominantly cardiac origin. Members of the NP system include ANP, BNP, CNP, VNP, their guanylate cyclase (GC)-linked receptors (NPR-A and NPR-B), and clearance receptor (NPR-C). Through the activation of their membrane-bound GC receptors, these small peptides modulate cellular functions that affect both salt and water balance. The elucidation of piscine NP sequences, structure, and functions has steadily advanced over the past 15 years spearheaded by research from Dr. Yoshio Takei's laboratory. The development of these homologous NPs has led to extensive research into both the evolutionary and physiological significance of NPs in fishes. One outcome has been the development of two seemingly disparate hypotheses of NP function; a role in salt excretion, the osmoregulatory hypothesis, versus a role in protecting the heart, the cardioprotective hypotheses. In the osmoregulatory hypothesis NPs are released in response to elevated ambient salinity and inhibit drinking and intestinal uptake of salt, thereby effectively reducing plasma sodium levels. In contrast, the cardioprotective theory depicts NPs acting to prevent debilitating cardiodilation from an excess of either venous or arterial pressure through vasodilation and a reduction of blood volume. These seemingly distinct hypotheses may be elements of a more general regulatory system and certainly require further investigation. Undoubtedly their resolution will not only give us a better perspective of the evolutionary basis of the NP system but will provide us with a greater appreciation of salt and water homeostasis in vertebrates.
Gen Comp Endocrinol 2008 May 15
PMID:Comparative physiology of the piscine natriuretic peptide system. 1847 99

Three guanylin-like peptides, guanylin, uroguanylin and renoguanylin and two guanylate cyclase type C (GC-C) receptor isoforms were cloned and sequenced from the European eel (Anguilla anguilla). All peptides and both receptors (GC-C1 and GC-C2) were predominantly expressed within the intestine and kidney of both sexually immature yellow, and sexually maturing, migratory silver eels. The derived amino acid sequences for the pre-prohormones and guanylate cyclase isoforms had structural features in common with sequences previously reported for guanylin-like peptides and guanylate cyclases from teleost fish and other species in general. The highest sequence homologies for the prohormones were found within the active, 15-16 amino acid C-terminal peptide domain, whereas the guanylate cyclase receptors exhibited highest homology throughout the transmembrane domain and intracellular region of the protein comprising the kinase homology, oligomerisation/coiled-coil and catalytic domains. In both yellow and silver eels, seawater (SW) acclimation induced sustained increases in the expression of uroguanylin and GC-C1 mRNAs within the intestine but no significant changes were found in the abundance of mRNAs for guanylin, renoguanylin or GC-C2. Likewise there were no significant changes in expression of any of the prohormone or receptor mRNAs within the renal kidney following transfer to SW. The results suggest that uroguanylin and GC-C1 are key components of a cGMP signalling system that may play an important role within intestinal enterocytes for the regulation of salt and water absorption in the SW-acclimated eel.
Gen Comp Endocrinol 2009 Mar
PMID:Guanylin-like peptides, guanylate cyclase and osmoregulation in the European eel (Anguilla anguilla). 1902 95

In goldfish, nitric oxide synthase (NOS) immunoreactivity is present in gonadotropes and extracellular signal-regulated protein kinase (ERK) mediates GnRH stimulation of gonadotropin release and synthesis. In this study, we tested the possible involvement of nitric oxide (NO) and ERK in mediating PACAP-stimulated maturational gonadotropin (GTH-II) release from primary cultures of dispersed goldfish pituitary cells. In static incubation experiments, PACAP-induced GTH-II release was unaffected by two inhibitors of NOS synthase, AGH and 1400W; whereas addition of a NO donor, SNAP, elevated GTH-II secretion. In perifusion experiments, neither NOS inhibitors (AGH, 1400W and 7-Ni) nor NO scavengers (PTIO and rutin hydrate) attenuated the GTH-II response to pulse applications of PACAP. In addition, the GTH-II responses to PACAP and the NO donor SNP were additive while PTIO blocked SNP action. Although dibutyryl cGMP increased GTH-II secretion in static incubation, inhibition of guanylate cyclase (GC), a known down-stream target for NO signaling, did not reduce the GTH-II response to pulse application of PACAP. On the other hand, GTH-II responses to PACAP in perifusion were attenuated in the presence of two inhibitors of ERK kinase (MEK), U 0126 and PD 98059. These results suggest that although increased availability of NO and cGMP can lead to increased GTH-II secretion, MEK/ERK signaling, rather than NOS/NO/GC activation, mediates PACAP action on GTH-II release in goldfish.
Gen Comp Endocrinol 2010 Jan 01
PMID:PACAP stimulation of maturational gonadotropin secretion in goldfish involves extracellular signal-regulated kinase, but not nitric oxide or guanylate cyclase, signaling. 1953 23


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