Inhibitor of adenosine 3':5'-monophosphate-dependent protein kinase blocks presynaptic facilitation in Aplysia

Abstract

Sensitization of the gill withdrawal reflex results from presynaptic facilitation at the excitatory synapses made by sensory neurons on gill motor neurons. Facilitation is accompanied by an increase in the duration of the action potential in sensory cells because of the depression of a K+ current. This results in an increasd influx of CA2+ and a greater release of transmitter from sensory neurons. There is evidence that serotonin is the facilitating transmitter and that the depression of the K+ current by serotonin mediated by cAMP-dependent protein phosphorylation. To test further the role of the cAMP-dependent protein kinase and of protein phosphorylation in sensitization, we have attempted to prevent or reverse the development of the electrophysiological correlates that accompany sensitization. We have pressure-injected sensory neurons with a specific and a stable protein inhibitor of the cAMP-dependent protein kinase both before and after the application of serotonin or the activation of the facilitator neurons. The increase in spike broadening that accompanies facilitation was prevented or diminished by injection of the inhibitor. Moreover, injection of the inhibitor could reverse fully the developed spike broadening produced by prior application of serotonin. These observations strenthen the evidence for the involvement of protein phosphorylation in presynaptic facilitation. Phosphorylation of the substrate protein evidently is quite labile and does not persist after the kinase is inhibited. Thus, the time course of short term sensitization appears to be determined by an active kinase. We think that it is likely that the mechanism for maintaining the kinase in an active form resides in the slow decay of the cAMP produced by the action of serotonin or the facilitator neurons on the sensory cells.

Altered axonal targeting and short-term plasticity in the hippocampus of Disc1 mutant mice

“…Elucidating whether cAMP signaling is involved is confounded by the facts that wholesale manipulations of cAMP levels through cAMP analogs and AC activation potently and bidirectionally affect release probability and result in diverse neurophysiological outputs at MFTs (48,49). Nevertheless, it is wellestablished that manipulating cAMP levels at various types of presynaptic terminals alters the dynamics of STP (50)(51)(52)(53). Of particular interest is that chronically elevated cAMP levels can affect synaptic facilitation through effects on vesicular pools (54), and animals lacking AC8, which acts as a presynaptic calcium sensor, have WM but not long-term memory deficits (55), similar to Disc1 Tm1Kara animals.…”

Postsynaptic Application of a Peptide Inhibitor of cAMP-Dependent Protein Kinase Blocks Expression of Long-Lasting Synaptic Potentiation in Hippocampal Neurons

“…Acute intracellular application of cell-impermeant, highly specific modifiers of PKA has been used successfully in other preparations to directly implicate protein kinases in modulating synaptic plasticity. In Aplysia, injection of PKI into sensory neurons innervating the gill blocked presynaptic facilitation induced by serotonin (Castellucci et al, 1982), whereas the injection of PKA catalytic subunits into the same neurons simulated presynaptic facilitation (Castellucci et al, 1980). In crayfish, injection of PKI into motoneurons blocked the late phase of long-term facilitation of neuromuscular transmission induced by tetanic stimulation (Dixon and Atwood, 1989).…”

Critical role for protein kinase A in the acquisition of gregarious behavior in the desert locust

“…Adenylyl cyclase/PKA signaling plays a central role in diverse forms of plasticity, including reflex sensitization, contextual fear conditioning, appetitive and aversive conditioning, and addiction (17,18,(21)(22)(23)(24)(25). PKA can phosphorylate both key proteins of the existing neuronal machinery (e.g., ion channels and synaptic proteins) to effect rapid but labile changes in behavior, and regulators of gene expression to effect changes that are slower but long-lasting.…”

“…A prominent effector mechanism in aminergic signaling is via adenylyl cyclase, resulting in the activation of cAMP-dependent protein kinase [protein kinase A (PKA)] (17)(18)(19)(20). Adenylyl cyclase/PKA signaling plays a central role in diverse forms of plasticity, including reflex sensitization, contextual fear conditioning, appetitive and aversive conditioning, and addiction (17,18,(21)(22)(23)(24)(25).…”