Mechanisms of PKA Dependent Regulation of Tomosyn

Tomosyn, a presynaptic inhibitor of neurotransmitter release, forms non-fusogenic SNARE complexes with the plasma membrane SNAREs, syntaxin and SNAP-25. While biochemical evidence indicates that vertebrate tomosyn is a direct PKA target, this has yet to be shown in the intact nervous system. However, there is a body of evidence indirectly supporting the role of PKA-dependent regulation of tomosyn in the nervous system, including the following observations: First, acute activation of cAMP phenocopies the tomosyn loss-of-function mutant, second, cAMP activation combined with tomosyn RNAi shows no additivity in the synaptic response, suggesting that they act in the same pathway. Furthermore, RNAi knockdown of Drosophila tomosyn disrupts PKA-dependent aversive olfactory learning. Together, these observations support a role for PKA-dependent regulation of tomosyn. However, whether this is due to a direct phosphorylation or an indirect pathway remains to be established. Recent evidence suggests that synapsin, also known to be regulated by PKA, may be playing a role in the regulation of tomosyn. This thesis evaluates both PKA-dependent and synapsin mediated regulation of tomosyn, providing further insights into tomosyn’s role in modulating synaptic plasticity.