Direct regulation of striated muscle myosins by nitric oxide and endogenous nitrosothiols.
BACKGROUND
Nitric oxide (NO) has long been recognized to affect muscle contraction, both through activation of guanylyl cyclase and through modification of cysteines in proteins to yield S-nitrosothiols. While NO affects the contractile apparatus directly, the identities of the target myofibrillar proteins remain unknown. Here we report that nitrogen oxides directly regulate striated muscle myosins.


RESULTS
Exposure of skeletal and cardiac myosins to physiological concentrations of nitrogen oxides, including the endogenous nitrosothiol S-nitroso-L-cysteine, reduced the velocity of actin filaments over myosin in a dose-dependent and oxygen-dependent manner, caused a doubling of force as measured in a laser trap transducer, and caused S-nitrosylation of cysteines in the myosin heavy chain. These biomechanical effects were not observed in response to S-nitroso-D-cysteine, demonstrating specificity for the naturally occurring isomer. Both myosin heavy chain isoforms in rats and cardiac myosin heavy chain from human were S-nitrosylated in vivo.


CONCLUSIONS
These data show that nitrosylation signaling acts as a molecular "gear shift" for myosin--an altogether novel mechanism by which striated muscle and cellular biomechanics may be regulated.
Evangelista
Alicia M
AM
Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America.
Rao
Vijay S
VS
Filo
Ashley R
AR
Marozkina
Nadzeya V
NV
Doctor
Allan
A
Jones
David R
DR
Gaston
Benjamin
B
Guilford
William H
WH
D000818:Animals; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009218:Myosins / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009603:Nitroso Compounds / Q000378:metabolism*; D051381:Rats; D013438:Sulfhydryl Compounds / Q000502:physiology*
D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D009218:Myosins