Upregulation of guanylyl cyclase expression and activity in striatum of MPTP-induced parkinsonism in mice.
The aim of our study was to investigate the expression and the activity of soluble guanylyl cyclase (GC) and phosphodiesterase (PDE) activities that regulate cGMP level in the striatum, hippocampus, and brain cortex in an animal model of PD, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We observed the increase of total activity and protein level of GC in striatum after MPTP injection. It was accompanied by an enhancement of both mRNA expression and protein level of GCbeta1 subunit. MPTP induces mRNA expression and elevates protein concentration of GCbeta1 in striatum up to 14 days after its injection, which in turn causes a marked enhancement of cGMP formation. Furthermore, the activation of GC occurs through change of maximal enzyme activity (V(max)). Simultaneously, no change in PDE activity has been detected in all investigated regions of the brain after MPTP. MPTP injection caused the elevation of GCbeta1 protein level in both the membrane and cytosol fractions being significantly higher in cytosol. Western blot analysis demonstrated about 45-67% decrease of tyrosine hydroxylase protein content in striatum. These data suggest that NO/cGMP signaling pathway may at least partially contribute to dopaminergic fiber degeneration in the striatum, the damage attributed to PD.
Department of Cellular Signaling, Medical Research Centre, Polish Academy of Sciences, Pawińskiego St. 5, 02-106 Warsaw, Poland. mchalim@yahoo.com <mchalim@yahoo.com>
Malgorzata
M
Chalimoniuk
Józef
J
Langfort
Nadezda
N
Lukacova
Józef
J
Marsala
D015056:1-Methyl-3-isobutylxanthine / Q000378:metabolism; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000818:Animals; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D006152:Cyclic GMP / Q000378:metabolism; D015259:Dopamine Agents / Q000633:toxicity*; D006162:Guanylate Cyclase / Q000235:genetics / Q000378:metabolism*; D020267:MPTP Poisoning / Q000201:enzymology*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015854:Up-Regulation
D015259:Dopamine Agents; D010726:Phosphodiesterase Inhibitors; D021122:Protein Subunits; D009569:Nitric Oxide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine