PERSISTENT ACTIVATION OF CAMP-DEPENDENT PROTEIN-KINASE BY REGULATED PROTEOLYSIS SUGGESTS A NEURON-SPECIFIC FUNCTION OF THE UBIQUITIN SYSTEMIN APLYSIA

In response to the facilitating neurotransmitter serotonin (5-HT), the cAMP-dependent protein kinase (PKA) acquires a special mnemonic chara cteristic in Aplysia sensory neurons, PKA becomes persistently activat ed at basal cAMP concentrations owing to a decreased regulatory (R) to catalytic (C) subunit ratio, We previously implicated ubiquitin-media ted proteolysis in this selective loss of R, Here we show that ubiquit in (Ub), Ub-conjugates and proteasomes are present in cell bodies, axo n, neuropil and nerve terminals of Aplysia neurons, Because R subunits are not decreased in muscle exposed to 5-HT, comparison of the two ti ssues provides a tractable approach to determine how the Ub pathway is regulated, We compared the structure of M1, the muscle-specific R iso form, to that of N4, a major neuronal R isoform, to rule out the possi bility that the differences in their stability result from differences in structure. We present evidence that N4 and M1 are encoded by ident ical transcripts; they also behave similarly as protein substrates for the Ub pathway in extracts of the two tissues, Nervous tissue contain s 20-times more free Ub, but we present evidence that the susceptibili ty of R subunits to degradation in neurons relative to muscle results from the greater capacity of neurons to degrade ubiquitinated proteins through the proteasome, Thus, factors that regulate the activity of p roteasomes could underlie the enhanced degradation of R subunits in lo ng-term sensitization.