Gating of CaMKII by cAMP-Regulated Protein Phosphatase Activity During LTP

Abstract

Long-term potentiation (LTP) at the Schaffer collateral-CA1 synapse involves interacting signaling components, including calcium (Ca2+)/calmodulin-dependent protein kinase II (CaMKII) and cyclic adenosine monophosphate (cAMP) pathways. Postsynaptic injection of thiophosphorylated inhibitor-1 protein, a specific inhibitor of protein phosphatase-1 (PP1), substituted for cAMP pathway activation in LTP. Stimulation that induced LTP triggered cAMP-dependent phosphorylation of endogenous inhibitor-1 and a decrease in PP1 activity. This stimulation also increased phosphorylation of CaMKII at Thr286 and Ca2+-independent CaMKII activity in a cAMP-dependent manner. The blockade of LTP by a CaMKII inhibitor was not overcome by thiophosphorylated inhibitor-1. Thus, the cAMP pathway uses PP1 to gate CaMKII signaling in LTP.

Theta-Frequency Synaptic Potentiation in CA1In VitroDistinguishes Cognitively Impaired from Unimpaired Aged Fischer 344 Rats

“…Putative mechanisms for theta-frequency LTP have been described previously (Blitzer et al, 1995(Blitzer et al, , 1998Thomas et al, 1996;Winder et al, 1999), but the basis for the AU-AI difference in 5 Hz LTP that we report is not known. One possible scenario could involve a difference in calcium channel signaling.…”

Whereas short-term facilitation is presynaptic, intermediate-term facilitation involves both presynaptic and postsynaptic protein kinases and protein synthesis

“…Presynaptic CamKII is also involved in all of the same effects as presynaptic PKA (including spike broadening) during sensitization in the siphon-withdrawal preparation (Antonov et al 2010), suggesting a possible linkage between the two preynaptic kinase pathways. There are several ways in which PKA is known to affect the CamKII pathway in this and other systems Schwartz 1983, 1985;Edmonds et al 1990;Blitzer et al 1998;Chang et al 2000), and CamKII might also affect the PKA pathway or the two kinases might phosphorylate common substrates. In addition, we found that postsynaptic Ca 2+ and CamKII contribute to facilitation by 10-min but not 1-min 5-HT, similar to the roles of postsynaptic Ca 2+ and CamKII in sensitization by four but not one shocks in the siphon-withdrawal preparation (Antonov et al 2010).…”

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

“…NMDA receptor-mediated currents are also increased by PKA-mediated phosphorylation (Raman et al, 1996;Leonard and Hell, 1997). PKA-mediated phosphorylation of a protein phosphatase inhibitor, I-1, could allow for the suppression of protein phosphatase-1, and the subsequent disinhibition of CaMKII may gate the expression of long-lasting LTP at postsynaptic sites (Blitzer et al, 1995(Blitzer et al, , 1998Brown et al, 2000). Finally, fusion proteins, consisting of PKI and nuclear localization signals, are capable of blocking long-lasting LTP in hippocampal slices when they are delivered into the nuclear compartment of neurons (Matsushita et al, 2001).…”