Characterization of particulate and soluble guanylate cyclases from rat lung

Chrisman, Ted D.; Garbers, D L; Parks, M A; Hardman, Joel G.

doi:10.1016/s0021-9258(19)41910-8

Cited by 215 publications

(9 citation statements)

References 14 publications

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“…Besides for the substrate MgGTP, sGC, like all adenylyl and guanylyl cyclases, requires a second metal ion as a cofactor (25). In the recently determined crystal structures of soluble AC (10,11), the binding site for this second metal ion has not been identified.…”

Section: Discussionmentioning

confidence: 99%

A Point-Mutated Guanylyl Cyclase with Features of the YC-1-Stimulated Enzyme: Implications for the YC-1 Binding Site?

et al. 1999

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Guanylyl cyclases (GCs) and adenylyl cyclases (ACs) play key roles in various signaling cascades and are structurally closely related. The crystal structure of a soluble AC revealed one binding site each for the substrate ATP and the activator forskolin. Recently, YC-1, a novel activator of the heterodimeric soluble GC (sGC), has been identified which acts like forskolin on AC. Here, we investigated the respective substrate and potential activator domains of sGC using point-mutated subunits. Whereas substitution of the conserved Cys-541 of the beta(1) subunit with serine led to an almost complete loss of activity, mutation of the respective homologue (Cys-596) in the alpha(1) subunit yielded an enzyme with an increased catalytic rate and higher sensitivity toward NO. This phenotype exhibits characteristics similar to those of the YC-1-treated wild-type enzyme. Conceivably, this domain which corresponds to the forskolin site of the ACs may comprise the binding site for YC-1.

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Section: Discussionmentioning

confidence: 99%

A Point-Mutated Guanylyl Cyclase with Features of the YC-1-Stimulated Enzyme: Implications for the YC-1 Binding Site?

et al. 1999

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“…Basal cGMP did not correlate with the relative activities of guanylate cyclase (highest in cortex) or cGMPphosphodiesterase (lowest in cortex) found in whole homogenates of the three tissues. Data from other tissues have suggested that the particulate form of guanylate cyclase may be a key determinant of cGMP economy in the intact cell due to its distinct properties Murad, 1974, 1975a,b; Garbers et al, 1975;Chrisman et al, 1975;. Accordingly, the present studies were conducted to define the subcellular distribution of guanylate cyclase and cGMP-phosphodiesterase activities in different regions of the kidney, and to characterize further the properties of the gua nylate cyclase-cGMP system of inner medulla.…”

mentioning

confidence: 95%

Properties and subcellular distribution of guanylate cyclase activity in rat renal medulla: correlation with tissue content of guanosine 3',5'-monophosphate

Craven¹,

DeRubertis²

1976

Biochemistry

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The properties of the guanylate cyclase systems of outer and inner medulla of rat kidney were examined and compared with those of the renal cortex. A gradation in steady-state cyclic guanosine 3',5'-monophosphate (cGMP) levels was observed in incubated slices of these tissues (inner medula greater than outer medulla greater than cortex). This correlated with the proportion of total guanyl cyclase activity in the 100 000 g particulate fraction of each tissue, but was discordant with the relative activities of guanylate cyclase (highest in cortex) and of cGMP-phosphodiesterase (lowest in cortex) in whole tissue homogenates. Soluble guanylate cyclase of cortex and inner medulla exhibited typical Michaelis-Menten kinetics with an apparent Km for MnGTP of 0.11 mM, while the particulate enzyme from inner medulla exhibited apparent positive cooperative behavior and a decreased dependence on Mn2+. Thus, the particulate enzyme could play a key role in regulating cGMP levels inthe intact cell where Mn2+ concentrations are low. The soluble and particulate enzymes from inner medulla were further distinguished by their responses to several test agents. The soluble enzyme was activated by Ca2+, NaN3, NaNo2 and phenylhydrazine, whereas particulate activity was inhibited by Ca2+ and was unresponsive to the latter agents. In the presence of NaNo2, Mn2+ requirement of the soluble enzyme was reduced and equivalent to that of the particulate preparation. Moreover, relative responsiveness of the sollble enzyme to NaNO2 was potentiated when Mg2+ replaced Mn2+ as the sole divalent cation. These changes in metal requirements may be involved in the action of NaNO2 to increase cGMP in intact kidney. Soluble guanylate cyclase of cortex was clearly more responsive to stimulation by NaN3, Nano2, and phenylhydrazine that was soluble activity from either medullary tissue. The effectiveness of the agonists on soluble activity from outer and inner medulla cound also be distinguished. Accordingly, regulation and properties of soluble guanylate cyclase, as well as subcellular enzyme distribution, and distinct in the three regions of the kidney.

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“…Following the convincing demonstration that cGMP production takes place both in the soluble and particulate fractions of rat heart and lung homogenates [2,3], the enormous number of studies carried out since then has established that the cyclic nucleotide is produced by two receptor-enzymes that differ in cellular localization, molecular structure, and mode of activation.…”

Section: The Cgmp Universe: Synthesis Signaling and Metabolismmentioning

confidence: 99%

Memory Enhancers for Alzheimer’s Dementia: Focus on cGMP

Fedele

Ricciarelli

2021

Pharmaceuticals

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Cyclic guanosine-3′,5′-monophosphate, better known as cyclic-GMP or cGMP, is a classical second messenger involved in a variety of intracellular pathways ultimately controlling different physiological functions. The family of guanylyl cyclases that includes soluble and particulate enzymes, each of which comprises several isoforms with different mechanisms of activation, synthesizes cGMP. cGMP signaling is mainly executed by the activation of protein kinase G and cyclic nucleotide gated channels, whereas it is terminated by its hydrolysis to GMP operated by both specific and dual-substrate phosphodiesterases. In the central nervous system, cGMP has attracted the attention of neuroscientists especially for its key role in the synaptic plasticity phenomenon of long-term potentiation that is instrumental to memory formation and consolidation, thus setting off a “gold rush” for new drugs that could be effective for the treatment of cognitive deficits. In this article, we summarize the state of the art on the neurochemistry of the cGMP system and then review the pre-clinical and clinical evidence on the use of cGMP enhancers in Alzheimer’s disease (AD) therapy. Although preclinical data demonstrates the beneficial effects of cGMP on cognitive deficits in AD animal models, the results of the clinical studies carried out to date are not conclusive. More trials with a dose-finding design on selected AD patient’s cohorts, possibly investigating also combination therapies, are still needed to evaluate the clinical potential of cGMP enhancers.

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Characterization of particulate and soluble guanylate cyclases from rat lung

Cited by 215 publications

References 14 publications

A Point-Mutated Guanylyl Cyclase with Features of the YC-1-Stimulated Enzyme: Implications for the YC-1 Binding Site?

A Point-Mutated Guanylyl Cyclase with Features of the YC-1-Stimulated Enzyme: Implications for the YC-1 Binding Site?

Properties and subcellular distribution of guanylate cyclase activity in rat renal medulla: correlation with tissue content of guanosine 3',5'-monophosphate

Memory Enhancers for Alzheimer’s Dementia: Focus on cGMP

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