Activation of purified guanylate cyclase by nitric oxide requires heme comparison of heme-deficient, heme-reconstituted and heme-containing forms of soluble enzyme from bovine lung

Ignarro, Louis J.; Degnan, Jonathan N.; Baricos, William H.; Kadowitz, Philip J.; Wolin, Michael S.

doi:10.1016/0304-4165(82)90008-3

Cited by 252 publications

(148 citation statements)

References 17 publications

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“…Organ culturing BPA with heme (hemin) reversed the attenuation of relaxation to NO under the conditions used to increase HO-1 expression. Early studies on NO regulation of sGC demonstrated that heme was easily lost as sGC was purified (8)(9)(10)(11)(18)(19)(20), suggesting that heme depletion could be a mechanism of regulating sGC stimulation by NO. Thus, the control of heme availability could be an important factor regulating the responsiveness of sGC and vascular tissue to NO.…”

Section: Discussionmentioning

confidence: 99%

“…Early studies on how nitric oxide (NO) regulates the soluble form of guanylate cyclase identified heme as an essential cofactor in mediating the stimulation of cGMP formation (8)(9)(10)(11)(18)(19)(20). These studies detected evidence for the presence of heme-containing and hemedeficient forms of sGC, where heme was easily lost from sGC as the enzyme was purified.…”

Section: Introductionmentioning

confidence: 99%

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Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide

Mingone¹,

Ahmad²,

Gupte³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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This study examines in endothelium-denuded bovine pulmonary arteries the effects of increasing heme oxygenase-1 (HO-1) activity on relaxation and soluble guanylate cyclase (sGC) activation by nitric oxide (NO). A 24 hour organ culture with 0.1 mM cobalt chloride (CoCl 2 ) or 30 μM Coprotoporphyrin IX was developed as a method of increasing HO-1 expression. These treatments increased HO-1 expression and HO activity by ~2-4 fold, and lowered heme levels by 40-45%. Induction of HO-1 was associated with an attenuation of pulmonary arterial relaxation to the NOdonor spermine-NONOate. The presence of a HO-1 inhibitor 30 μM chromium mesoporphyrin during the 24 hour organ culture (but, not acute treatment with this agent) reversed the attenuation of relaxation to NO seen in arteries co-cultured with agents that increased HO-1. Relaxation to isoproterenol, which is thought to be mediated through cAMP, was not altered in arteries with increased HO-1. Inducers of HO-1 did not appear to alter basal sGC activity in arterial homogenates or expression of the β1-subunit of sGC. However, the increase in activity seen in the presence of 1 μM spermine-NONOate was attenuated in homogenates obtained from arteries with increased HO-1. Since arteries with increased HO-1 had decreased levels of superoxide detected by the chemiluminescence of 5 μM lucigenin, superoxide did not appear to be mediating the attenuation of relaxation to NO. These data suggest that increasing HO-1 activity depletes heme, and this is associated with an attenuation of pulmonary artery relaxation and sGC activation responses to NO.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide

Mingone¹,

Ahmad²,

Gupte³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…The Nterminal portion of each subunit constitutes a heme-binding domain and represents the least conserved region of the protein; it is the heme moiety that confers the NO-sensitivity of the enzyme. 58 Heme-reconstituted sGC can be activated nearly 100-fold by NO. 58 Soluble GC may contain 1 mole of heme bound per monomer, depending on the purification protocol.…”

Section: The No Receptor: Soluble Guanylate Cyclasementioning

confidence: 99%

Nitric oxide–cyclic GMP pathway with some emphasis on cavernosal contractility

Ghalayini

2004

Int J Impot Res

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Nitric oxide (NO) is formed from the conversion of L-arginine by nitric oxide synthase (NOS), which exists in three isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). nNOS is expressed in penile neurons innervating the corpus cavernosum, and eNOS protein expression has been identified primarily in both cavernosal smooth muscle and endothelium. NO is released from nerve endings and endothelial cells and stimulates the activity of soluble guanylate cyclase (sGC), leading to an increase in cyclic guanosine-3 0 ,5 0 -monophosphate (cGMP) and, finally, to calcium depletion from the cytosolic space and cavernous smooth muscle relaxation. The effects of cGMP are mediated by cGMP dependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesterases (PDE). Thus, cGMP effect depends on the expression of a cell-specific cGMPreceptor protein in a given cell type. Numerous systemic vasculature diseases that cause erectile dysfunction (ED) are highly associated with endothelial dysfunction, which has been shown to contribute to decreased erectile function in men and a number of animal models of penile erection. Based on the increasing knowledge of intracellular signal propagation in cavernous smooth muscle tone regulation, selective PDE inhibitors have recently been introduced in the treatment of ED. Phosphodiesterase 5 (PDE5) inactivates cGMP, which terminates NO-cGMP-mediated smooth muscle relaxation. Inhibition of PDE5 is expected to enhance penile erection by preventing cGMP degradation. Development of pharmacologic agents with this effect has closely paralleled the emerging science.

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“…The NO sensitivity of the mammalian enzyme is dependent on the presence of hematin; responsiveness can be eliminated by stripping away heme groups, and reconstituted by adding them back (Craven and DeRubertis, 1978;Ignarro et al, 1982). We added hematin, protoporphyrin 9 (a heme precursor), or hemocyanm (a copper-containing, heme-like respiratory pigment found in many invertebrates) to lobster nerve…”

Section: The Crustacean Cytoplasmic Cyclase Responds Weakly To Nomentioning

confidence: 99%

“…These cyclases are activated by a transduction pathway that involves free radical signaling agents (Waldman and Murad, 1987;Garthwaite and Boulton, 1995), which interact with prosthetic herne groups attached to the holoenzyme (Craven and DeRubertis, 1978;Ignarro et al, 1982). Nitric oxide (NO) is the most widely recognized free radical activator, but similar roles have been proposed for carbon monoxide (Ingi and Ronnett, 1995;Ingi et al, 1996) and polyunsaturated fatty acids (such as arachidonate and/or its metabolites) (Waldman and Murad, 1987).…”

mentioning

confidence: 99%

Identification of Nitric Oxide‐Sensitive and ‐Insensitive Forms of Cytoplasmic Guanylate Cyclase

Prabhakar

Short

Scholz

et al. 1997

Journal of Neurochemistry

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Cytoplasmic, nitric oxide-activated guanylate cyclases are expressed in many regions of the mammaian brain and are thought to participate in functions as diverse as synaptogenesis and long-term potentiation. In this study, we have characterized cytoplasmic guanylate cyclases in the nervous system of an invertebrate, the American lobster. Cytoplasmic cyclase specific activity is higher in lobster nerve cord than in any other lobster tissue tested, and considerably higher than in typical rat tissues (cerebellum, lung, and liver). However, nitric oxide donors have minimal effects on lobster nerve cord cyclic GMP production, when applied either to intact tissue or to cytoplasmic extracts. Parallel immunocytochemical studies, using an anti-cyclic GMP antibody, reveal that only a small subset of lobster neurons responds to nitric oxide with a significant elevation of cyclic GMP levels. HPLC analysis of nerve cord cytoplasm reveals two chromatographically separable cyclases, a minor nitric oxide-sensitive form whose retention time is identical to that of the conventional mammalian enzyme and a more abundant nitric oxide-insensitive form that appears to be novel. The physiological function and phylogenetic distribution of this nitric oxide-insensitive enzyme, and the signaling mechanisms that regulate its activity, are not known.

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Activation of purified guanylate cyclase by nitric oxide requires heme comparison of heme-deficient, heme-reconstituted and heme-containing forms of soluble enzyme from bovine lung

Cited by 252 publications

References 17 publications

Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide

Heme oxygenase-1 induction depletes heme and attenuates pulmonary artery relaxation and guanylate cyclase activation by nitric oxide

Nitric oxide–cyclic GMP pathway with some emphasis on cavernosal contractility

Identification of Nitric Oxide‐Sensitive and ‐Insensitive Forms of Cytoplasmic Guanylate Cyclase

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