AGE-RELATED ALTERATION IN SIGNAL-TRANSDUCTION - INVOLVEMENT OF THE CAMP CASCADE

In the present study, we have investigated the involvement of the cAMP signal transduction pathways in young and aged rats. A significantly higher endogenous adenosine 3':5'-cyclic monophosphate (cAMP) level an d a significant decline of the adenylate cyclase [AC, ATP pyrophosphat e-lyase (cyclizing), EC 4.6.1.1.] activity were observed in striatal t issue from young rats (3 months) in comparison to aged rats (approxima tely 40 months). In the nucleus accumbens (NA), no age-dependent chang es in the cAMP concentration and in the AC basal activity were found. To address the question, whether the interactions of guanine nucleotid e-binding protein (G-protein) subunits (G(alphas) and G(i)) with AC ha ve changed in the aging process, various pharmacological agents that m odulate the AC activity (e.g., beta, tau-imidoguanine 5'-triphosphate (GppNHp), sodium fluoride (NaF), forskolin (FSK), and the combinations of GppNHp plus FSK, NaF plus FSK, and NaF plus ethanol (ETOH)) were a pplied. In addition, a [H-3]FSK binding test was carried out. In stria tal and NA tissue, the stimulation of the AC activity by FSK was inhib ited by GppNHp (via G(i)-protein) and was superadditive by the combina tion of FSK and NaF (via G(s)-protein). The absolute AC activity upon stimulation by all agents used was significantly lower in the aged str iatum compared to young striatum. In the NA, however, the AC activity showed an age-dependent reduction only upon FSK and upon FSK plus GppN Hp stimulation. There was no difference in the specific [H-3]FSK bindi ng to the G(alphas) protein-coupled catalytic subunit of the AC betwee n young and aged animals both in the striatum and NA. Apparently, the age-related decline of the AC activity was independent of a change of G(s) and G(i) activity. The involvement of the cAMP signal transmissio n in the aging process was demonstrated also in the NA, yet it was les s pronounced than in the striatum.