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The Journal of Neuroscience, March 28, 2007, 27(13):3439-3444; doi:10.1523/JNEUROSCI.5612-06.2007

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Brief Communications
Regulation of Protein Kinase M Synthesis by Multiple Kinases in Long-Term Potentiation

Matthew Taylor Kelly,^1,2 John Fonda Crary,^1,2 and Todd Charlton Sacktor¹

¹Departments of Physiology, Pharmacology, and Neurology, and ²Graduate Program in Neural and Behavioral Sciences, The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, New York, 11203

Correspondence should be addressed to Dr. Todd C. Sacktor, Dept of Physiology and Pharmacology, Box 29, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203. Email: tsacktor{at}downstate.edu

The persistent activity of protein kinase M (PKM) maintains synaptic long-term potentiation (LTP) and spatial memory, but the interactions between PKM and the other protein kinases implicated in synaptic plasticity are unknown. During LTP, PKM is rapidly synthesized from a PKM mRNA that encodes a protein kinase C (PKC) catalytic domain without a regulatory domain; thus, second messengers that activate full-length PKC isoforms are not required to stimulate PKM. Like other PKCs, however, PKM must be phosphorylated on its activation loop by phosphoinositide-dependent protein kinase-1 (PDK1) for optimal catalytic activity. Thus, two sequential steps are required for the persistent increased PKM activity that maintains LTP: de novo synthesis of PKM and phosphorylation of its activation loop. Here, using a panel of antisera to phosphorylated and nonphosphorylated sites on PKM, we show that PI3-kinase (phosphoinositide 3-kinase), CaMKII (Ca²⁺/calmodulin-dependent protein kinase II), MAPK (mitogen-activated protein kinase), PKA (protein kinase A), mTOR (mammalian target of rapamycin), all important for LTP induction, as well as preexisting PKM, regulate the new synthesis of PKM during LTP. In contrast, PDK1 forms a complex with PKM and maintains maximal phosphorylation of its activation loop. Thus, the two steps of PKM formation serve separate functions in LTP: the initial regulated synthesis of PKM is the site of convergence and integration for multiple kinases of induction, whereas the constitutive phosphorylation of PKM by PDK1 initiates the persistent autonomous activity that sustains maintenance.

Key words: CaMKII; ERK; learning and memory; LTP; long-term potentiation; phosphoinositide 3-kinase; protein synthesis

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Received Dec. 26, 2006; revised Feb. 21, 2007; accepted Feb. 23, 2007.

Correspondence should be addressed to Dr. Todd C. Sacktor, Dept of Physiology and Pharmacology, Box 29, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203. Email: tsacktor{at}downstate.edu

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