title: Age-related changes in cyclic GMP and PKG-stimulated cerebellar Na,K-ATPase activity.
abstract: Energy deficiency and dysfunction of the Na,K-ATPase are common consequences of many pathological insults. Glutamate through cyclic GMP and cyclic GMP-dependent protein kinase (PKG) has been shown to stimulate alpha(2/3)-Na,K-ATPase activity in the central nervous system. Thus, a slight impairment of this pathway may amplify the disruption of ion homeostasis in the presence of a non-lethal insult. We investigate the effect of aging (4, 12 and 24 months) on the glutamate-cyclic GMP-PKG modulation of alpha1, alpha(2/3)-Na,K-ATPase activity in rat cerebellum and the stimulation of the glutamate-cyclic GMP-PKG pathway at different levels. Cyclic GMP levels and alpha(2/3)-Na,K-ATPase activity were progressively decreased from 4 and 24 month-old animals. However, PKG basal activity was reduced between 4 and 12 months, and no additional change was observed at 24 months. The ability of 8-Br-cyclic GMP to stimulate PKG activity was only reduced between 12 and 24 months. Moreover, glutamate or 8-Br-cyclic GMP promoted a smaller increase of alpha(2/3)-Na,K-ATPase activity at 24 months, when compared to 4 and 12 months. In spite of the age-related reduced basal levels of cyclic GMP, the production induced by CO or NO was not age-related. Finally, inhibition of PKG activation by KT5823 revealed a lower sensitivity of the enzyme at the older age. Taken together, these data show that basal age-related decline in sodium pump activity is a consequence of changes in different steps of the cyclic GMP-PKG pathway. On the other hand, age-related reduction in glutamate positive modulation of cerebellar alpha(2/3)-Na,K-ATPase is linked to a defective PKG signaling pathway.
authors.affiliation: Department of Pharmacology, Institute of Biomedical Science University of São Paulo Avenida Lineu Prestes, São Paulo 152405508-900, Brazil. criscavone@usp.br
authors.forename: Cristoforo
authors.initials: C
authors.lastname: Scavone
authors.forename: Carolina Demarchi
authors.initials: CD
authors.lastname: Munhoz
authors.forename: Elisa Mitiko
authors.initials: EM
authors.lastname: Kawamoto
authors.forename: Isaias
authors.initials: I
authors.lastname: Glezer
authors.forename: Larissa
authors.initials: L
authors.lastname: de Sá Lima
authors.forename: Tania
authors.initials: T
authors.lastname: Marcourakis
authors.forename: Regina Pekelmann
authors.initials: RP
authors.lastname: Markus
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000375:Aging / Q000378:metabolism*; D000818:Animals; D002531:Cerebellum / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D015398:Signal Transduction / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
chemical_list: D017869:Cyclic GMP-Dependent Protein Kinases; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP