Vasomodulation by skeletal muscle-derived nitric oxide requires alpha-syntrophin-mediated sarcolemmal localization of neuronal Nitric oxide synthase.
Neuronal nitric oxide synthase (nNOS) is abundantly expressed in skeletal muscle where it associates with the dystrophin complex at the sarcolemma by binding to the PDZ domain of alpha-syntrophin. Nitric oxide (NO) produced by skeletal muscle nNOS is proposed to regulate blood flow in exercising muscle by diffusing from the skeletal muscle fibers to the nearby microvessels where it attenuates alpha-adrenergic vasoconstriction. In the present study, we hypothesized that sarcolemmal localization of nNOS is a critical determinant of the vasoregulatory effect of skeletal muscle-derived NO. To test this hypothesis, we performed experiments in alpha-syntrophin null mice and in transgenic mice expressing a mutated alpha-syntrophin lacking the PDZ domain (DeltaPDZ), both of which are characterized by reduced sarcolemmal nNOS. We found that modulation of alpha-adrenergic vasoconstriction was greatly impaired in the contracting muscles of the alpha-syntrophin null mice and transgenic DeltaPDZ mice compared with wild-type mice and transgenic mice expressing full-length alpha-syntrophin. These in vivo mouse studies highlight the functional importance of appropriate membrane targeting of nNOS by the dystrophin-associated protein alpha-syntrophin and may have implications for the development of potential gene therapy strategies to treat muscular dystrophy or other muscle-related diseases.
Thomas
Gail D
GD
Department of Internal Medicine, Division of Hypertension, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Tex 75390-8586, USA. gail.thomas@utsouthwestern.edu
Shaul
Philip W
PW
Yuhanna
Ivan S
IS
Froehner
Stanley C
SC
Adams
Marvin E
ME
D000818:Animals; D002135:Calcium-Binding Proteins; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009119:Muscle Contraction; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000032:analysis*; D052248:Nitric Oxide Synthase Type I; D009638:Norepinephrine / Q000494:pharmacology; D010641:Phenotype; D017434:Protein Structure, Tertiary; D012508:Sarcolemma / Q000201:enzymology*; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D002135:Calcium-Binding Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D014662:Vasoconstrictor Agents; C091825:syntrophin alpha1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D009638:Norepinephrine