: The importance of studying synaptic functions at the molecular level is most obvious for understanding mental and neurological diseases where psychopharmacological therapeutics, modern molecular genetics and biochemically-oriented neuropathology suggest an underlying synaptic malady. Long-term presynaptic facilitation of sensory-to-motor, synapses, which is a form of plasticity underlying behavioral sensitization in the marine mollusk Aplysia and an elementary form of learning, can be produced by the action of the cAMP-dependent protein kinases (PKA). A decrease of about 25% in the regulatory (R) subunits of PKA occurs in sensory neurons when treated to produce long-term facilitation; this molecular change endures only if new protein is made. No change in catalytic (C) subunits occurs. A decreased R/C ratio produces a kinases more sensitive to subsaturating cAMP and sets the baseline extent of protein phosphorylation within the neuron at a higher level for at least 24 h; this change could be the molecular phosphorylation within the neuron at a higher level for at least 24 h; this change could be the molecular mechanism underlying an intermediary form of memory. The fine control of cAMP-dependent phosphorylation is mediated by regulated proteolysis through the ubiquitin-proteasome pathway, which degrades R Subunits selectively. During the development of long-term facilitation, persistent protein phosphorylation results in the enhancement of synaptic strength by increasing the output of neurotransmitter at existing synapses; later, the memory is consolidated by normal output of transmitter at an increased number of new synapses. Our working idea is that signal transduction by a facilitation transmitter (e.g., serotonin) activates PKA, which then triggers a molecular cascade in the nucleus involving cAMP-reactive elements for transcription activator proteins and effector proteins, one or more of which alter the ubiquitin-proteasome pathway in sensory neurons. A ubiquitin carboxyl-terminal hydrolase and elongation factor 1a, two proteins that are induced during long-term facilitation, have been implicated in proteasome function in other system.
Our first aim i s to show, using specific proteasome inhibitors, that the ubiquitin-proteasome pathway is needed for long-term facilitation.
Our second aim i s to determine whether the induced hydrolase and elongation factor facilitate proteolysis by proteasomes.
| Kurosu, Takeshi; Hernandez, A Ivan; Wolk, Jason et al. (2009) Alpha/beta-tubulin are A kinase anchor proteins for type I PKA in neurons. Brain Res 1251:53-64 |
| Kurosu, Takeshi; Hernandez, A Ivan; Schwartz, James H (2007) Serotonin induces selective cleavage of the PKA RI subunit but not RII subunit in Aplysia neurons. Biochem Biophys Res Commun 359:563-7 |
