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5 results on '"Lane, Paul B."'

1. Molecular regulation of endothelial nitric oxide synthase

Author

Lane, Paul B.

Subjects
615.1, Calmodulin, CaM, NOS
Abstract

The three isoforms of nitric oxide synthase (NOS) are classified based on their mode of regulation by calmodulin (CaM). The "calcium-independent" inducible isoform (iNOS) contains tightly-bound CaM and is active at all levels of intracellular calcium. In contrast, the two calcium-dependent isoforms (neuronal, nNOS and endothelial eNOS) are activated by CaM-binding following stimulus-evoked increases in intracellular calcium. However, both the structural basis for these differences in regulation and the molecular basis for CaM-induced cNOS activation remained unclear. Given that the regulation of calmodulin regulated enzyme systems often involves the displacement of an intrinsic autoinhibitory domain, we attempted to identify regions of eNOS which may fulfill this autoinhibory function. Herein, I describe the identification of two autoinhibitory control elements (ACEs) in eNOS, one within the FMN binding domain (ACE-I) and one located at the C-terminus (ACE-2). Together with CaM, these form a tripartite system for the regulation of eNOS. ACE-lIACE-2 exerting negative effects to attenuate catalytic activity, which are overcome by the conformational changes induced by CaM-binding. The mechanism of ACE-lIACE-2-mediated inhibition and the alleviation of this inhibition were investigated.

Published
2000

2. Profound biopterin oxidation and protein tyrosine nitration in tissues of ApoE-null mice on an atherogenic diet: contribution of inducible nitric oxide synthase

Author

Upmacis, Rita K., Crabtree, Mark J., Deeb, Ruba S., Shen, Hao, Lane, Paul B., Benguigui, Lea Esther S., Maeda, Nobuyo, Hajjar, David P., and Gross, Steven S.

Subjects
Coenzymes -- Properties, Protein tyrosine kinase -- Properties, Apolipoproteins -- Properties, Nitric oxide -- Influence, Nitric oxide -- Physiological aspects, Mice -- Food and nutrition, Mice -- Physiological aspects, Biological sciences
Abstract

Diminished nitric oxide (NO) bioactivity and enhanced peroxynitrite formation have been implicated as major contributors to atherosclerotic vascular dysfunctions. Hallmark reactions of peroxynitrite include the accumulation of 3-nitrotyrosine (3-NT) in proteins and oxidation of the NO synthase (NOS) cofactor, tetrahydrobiopterin (B[H.sub.4]). The present study sought to 1) quantify the extent to which 3-NT accumulates and [BH.sub.4] becomes oxidized in organs of apolipoprotein E-deficient ([ApoE.sup.-/-]) atherosclerotic mice and 2) determine the specific contribution of inducible NOS (iNOS) to these processes. Whereas protein 3-NT and oxidized B[H.sub.4] were undetected or near the detection limit in heart, lung, and kidney of 3-wk-old [ApoE.sup.-/-] mice or [ApoE.sup.-/-] mice fed a regular chow diet for 24 wk, robust accumulation was evident after 24 wk on a Western (atherogenic) diet. Since 3-NT accumulation was diminished 3- to 20-fold in heart, lung, and liver in [ApoE.sup.-/-] mice missing iNOS, iNOS-derived species are involved in this reaction. In contrast, iNOS-derived species did not contribute to elevated protein 3-NT formation in kidney or brain, iNOS deletion also afforded marked protection against B[H.sub.4] oxidation in heart, lung, and kidney of atherogenic [ApoE.sup.-/-] mice but not in brain or liver. These findings demonstrate that iNOS-derived species are increased during atherogenesis in [ApoE.sup.-/-] mice and that these species differentially contribute to protein 3-NT accumulation and B[H.sub.4] oxidation in a tissue-selective manner. Since B[H.sub.4] oxidation can switch the predominant NOS product from NO to superoxide, we predict that progressive NOS uncoupling is likely to drive atherogenic vascular dysfunctions. inducible nitric oxide synthase; high-fat diet

Published
2007

3. MOLECULAR REGULATION OF ENDOTHELIAL NITRIC OXIDE SYNTHASE

Author

Lane, Paul B

Abstract

The three isoforms of nitric oxide synthase (NOS) are classified based on their mode of regulation by calmodulin (CaM). The "calcium-independent" inducible isoform (iNOS) contains tightly-bound CaM and is active at all levels of intracellular calcium. In contrast, the two calcium-dependent isoforms (neuronal, nNOS and endothelial eNOS) are activated by CaM-binding following stimulus-evoked increases in intracellular calcium. However, both the structural basis for these differences in regulation and the molecular basis for CaM-induced cNOS activation remained unclear. Given that the regulation of calmodulin regulated enzyme systems often involves the displacement of an intrinsic autoinhibitory domain, we attempted to identify regions of eNOS which may fulfill this autoinhibory function. Herein, I describe the identification of two autoinhibitory control elements (ACEs) in eNOS, one within the FMN binding domain (ACE-I) and one located at the C-terminus (ACE-2). Together with CaM, these form a tripartite system for the regulation of eNOS. ACE-lIACE-2 exerting negative effects to attenuate catalytic activity, which are overcome by the conformational changes induced by CaM-binding. The mechanism of ACE-lIACE-2-mediated inhibition and the alleviation of this inhibition were investigated.

Published
2000

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