Neuronal Nitric-oxide Synthase-μ, an Alternatively Spliced Isoform Expressed in Differentiated Skeletal Muscle

Silvagno, Francesca; Xia, Houhui; Bredt, David S.

doi:10.1074/jbc.271.19.11204

Cited by 328 publications

(215 citation statements)

References 28 publications

(33 reference statements)

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“…12,13 We have found that these two isoforms exist in different proportions in the lower urinary tract, skeletal muscle and the penis. In this study, we found a signi®cant down-regulation of only the large form of nNOS in the diabetic rats but not the small form.…”

Section: Discussionmentioning

confidence: 99%

Effects of diabetes on nitric oxide synthase and growth factor genes and protein expression in an animal model

et al. 1999

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Erectile dysfunction occurs frequently in humans with diabetes mellitus; the molecular basis of this phenomenon is not known. We investigated the effects of diabetes on penile erection, nitric oxide synthase and growth factors expression in an animal model. Forty male rats were divided into two groups: the experimental group (n 30) received intraperitoneal injection of Streptozotocin (STZ) dissolved in citrate buffer to induce diabetes; ten age-matched control rats received injection of citrate buffer vehicle only. Before euthanization at eight weeks, erectile function was assessed by electrostimulation of the cavernous nerves. NADPH diaphorase staining was used to identify NOS and immunostaining technique was used to identify nNOS in the penile nerve ®bers. RT-PCR was used to identify mRNA expression of nNOS, eNOS, iNOS, ER-b b, ER-a, NGF, IGF-I, TGF-b1, and AR. Western blot was used to identify nNOS, IGF-I, NGF, and TFG-b protein expressions. In the diabetic group, there was: (1) a signi®cant decrease in NOS containing nerve ®bers in the dorsal and intracavernosal nerves; (2) a signi®cant lower maximal intracavernosal pressure. RT-PCR showed down-regulation of nNOS (large form), iNOS and ER-b mRNA expression, Immunoblot showed down-regulation of nNOS protein expression and nNOS immunostaining showed less positive staining in the dorsal and intracavernous nerves in the diabetic group. These molecular changes may provide the basis for further studies to explore the association between diabetes and impotence.

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Section: Discussionmentioning

confidence: 99%

Effects of diabetes on nitric oxide synthase and growth factor genes and protein expression in an animal model

et al. 1999

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“…The increases in intracellular Ca 2+ that occur upon muscle excitation increase basal nNOS activity several fold during contraction . Skeletal muscles express two alternatively spliced nNOS isoforms, nNOSμ and nNOSβ, both of which are expressed in fast and slow muscle types (Silvagno et al 1996;Stamler and Meissner 2001;Percival et al 2010, Figure 1). nNOSμ is scaffolded to the subsarcolemmal dystrophin glycoprotein complex (DGC) and neuromuscular junction (Brenman et al 1995(Brenman et al , 1996Adams et al 2000).…”

Section: Introductionmentioning

confidence: 99%

nNOS regulation of skeletal muscle fatigue and exercise performance

Percival

2011

Biophys Rev

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Neuronal nitric oxide synthases (nNOS) are Ca 2+ /calmodulin-activated enzymes that synthesize the gaseous messenger nitric oxide (NO). nNOSμ and the recently described nNOSβ, both spliced nNOS isoforms, are important enzymatic sources of NO in skeletal muscle, a tissue long considered to be a paradigmatic system for studying NO-dependent redox signaling. nNOS is indispensable for skeletal muscle integrity and contractile performance, and deregulation of nNOSμ signaling is a common pathogenic feature of many neuromuscular diseases. Recent evidence suggests that both nNOSμ and nNOSβ regulate skeletal muscle size, strength, and fatigue resistance, making them important players in exercise performance. nNOSμ acts as an activity sensor and appears to assist skeletal muscle adaptation to new functional demands, particularly those of endurance exercise. Prolonged inactivity leads to nNOS-mediated muscle atrophy through a FoxO-dependent pathway. nNOS also plays a role in modulating exercise performance in neuromuscular disease. In the mdx mouse model of Duchenne muscular dystrophy, defective nNOS signaling is thought to restrict contractile capacity of working muscle in two ways: loss of sarcolemmal nNOSμ causes excessive ischemic damage while residual cytosolic nNOSμ contributes to hypernitrosylation of the ryanodine receptor, causing pathogenic Ca 2+ leak. This defect in Ca 2+ handling promotes muscle damage, weakness, and fatigue. This review addresses these recent advances in the understanding of nNOS-dependent redox regulation of skeletal muscle function and exercise performance under physiological and neuromuscular disease conditions.

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“…Transcripts resulting from the alternative splicing of a gene are not an uncommon occurrence. For example, the constitutive forms of the hemoprotein, NO synthase [9-111 in the brain and muscle are the products of alternatively spliced transcripts and differ only by a short sequence of internal amino acids [12]. Also, we were inquisitive as to whether there exist additional form(s) of HO in biological systems, as is the case with many heme-related proteins.…”

mentioning

confidence: 99%

Isolation and Characterization of a cDNA from the Rat Brain that Encodes Hemoprotein Heme Oxygenase‐3

McCoubrey¹,

Huang²,

Maines³

1997

European Journal of Biochemistry

773

469

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Two isozymes of heme oxygenase (HO), HO-1 or HSP32 and the constitutive form HO-2, have been characterized to date. We report the discovery of a third protein species and refer to it as HO-3. HO-3 is the product of a single transcript of ~2 . 4 kb and can encode a protein of =33 kDa. The HO-3 transcript is found in the spleen, liver, thymus, prostate, heart, kidney, brain and testis and is the product of a singlecopy gene. The predicted amino acid structure of HO-3 differs from both HO-1 (HSP32) and HO-2 but is closely related to HO-2 (~9 0 % ) .Escherichia coli expressed and purified HO-3 protein does not cross react with polyclonal antibodies to either rat HO-1 or HO-2, is a poor heme catalyst, and displays hemoprotein spectral characteristics. The predicted protein has two heme regulatory motifs that may be involved in heme binding. These motifs and the hemoprotein nature of HO-3 suggest a potential regulatory role for the protein in cellular processes which are heme-dependent.

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Neuronal Nitric-oxide Synthase-μ, an Alternatively Spliced Isoform Expressed in Differentiated Skeletal Muscle

Cited by 328 publications

References 28 publications

Effects of diabetes on nitric oxide synthase and growth factor genes and protein expression in an animal model

Effects of diabetes on nitric oxide synthase and growth factor genes and protein expression in an animal model

nNOS regulation of skeletal muscle fatigue and exercise performance

Isolation and Characterization of a cDNA from the Rat Brain that Encodes Hemoprotein Heme Oxygenase‐3

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