Tonically active protein kinase A regulates neurotransmitter release at the squid giant synapse

1. Electrophysiological and microinjection methods were used to examine the role of cyclic AMP dependent protein kinase A (PKA) in regulating transmit ter release at the squid giant synapse. 2. Excitatory postsynaptic potentials (EPSPs) evoked by presynaptic action potentials were not affected by presynaptic injection of an exogenous activ e catalytic subunit of mammalian PKA. 3. In contrast, presynaptic injection of PKI-amide, a peptide that inhibits PKA with high potency and specificity, led to a reversible inhibition of E PSPs. 4. Injection of several other peptides that serve as substrates for PKA als o reversibly inhibited neurotransmitter release. The ability of these pepti des to inhibit release was correlated with their ability to serve as PKA su bstrates, suggesting that these peptides act by competing with endogenous s ubstrates for phosphorylation by active endogenous PKA. 5. We suggest that the phosphorylation of PKA substrates is maintained at a relatively high state under basal conditions and that this tonic activity of PKA is to a large degree required fur evoked neurotransmitter release at the squid giant presynaptic terminal.