PKCλ: a new player in LTP coming to the rescue of PKCζ's faltering role in LTP?

Long-term potentiation (LTP) of synaptic transmission has received widespread attention because it is thought to form the physiological basis of learning and memory. A new paper in The EMBO Journal identifies the atypical PKC family member PKCl as an important contributor to the strengthening of the postsynaptic response in LTP. Synaptic transmission in the brain is largely mediated by presynaptic glutamate release and postsynaptic activation of AMPA-type glutamate receptors (AMPARs). LTP is a permanent increase in synaptic transmission at individual synapses following a brief period of strongly enhanced synchronous activity of the very synapses and of the neurons the synapses connect (Lisman and Hell, 2008). LTP is typically mediated by an increase in postsynaptic AMPAR activity and requires Ca flux through NMDA-type glutamate receptors (NMDARs) and the ensuing stimulation of CaMKII and, at least in certain cases, of PKC (Lisman and Hell, 2008). The PKC family consists of ‘conventional’ PKCa, b, and g, which are activated by Ca -induced binding of anionic phospholipid to their C2 domains and by binding of diacylglyerol (DAG) to their C1 domains, ‘novel’ PKCd and e, which are activated by DAG, and ‘atypical’ PKCz and rodent PKCl/ human PKCi, which are activated by lipids such as PIP3 or ceramide via binding to their unorthodox C1 domains (Steinberg, 2008). Proteolytic processing as well as differential splicing can give rise to constitutively active PKC isoforms (PKMs) that lack the regulatory domain including their inhibitory pseudosubstrate segments. Expression of PKMz, which is formed by translation of an alternative transcript of the PKCz gene, is induced by LTP whereas the full-length PKCz gene product is usually undetectable in the hippocampus (Hernandez et al, 2003). PKMz has been implicated in the maintenance of LTP and memory (e.g., Ling et al, 2002; Pastalkova et al, 2006). Part of this evidence stems from the inhibition of LTP by the membrane-permeant myristoylated peptide ZIP that is derived from the autoinhibitory pseudosubstrate segment of PKCz. However, the pseudosubstrate segment of PKCz is identical to that of PKCl raising the possibility that ZIP might also inhibit PKCl and exert some of its effects by antagonizing PKCl rather than PKCz. In fact, pursuing this notion, the new work by Ren et al (2013) shows that 2 mM ZIP, which they call Myr-aPKC-PS, blocks not only PKMz but also PKCl. Application of ZIP/Myr-aPKC-PS resulted in short-lived LTP that decayed to baseline within 20min after its induction in CA1 pyramidal cells. Knockdown (KD) of PKCl also rendered LTP short-lived. Direct stimulation of PI3K, which generates PIP3, increased PKCl activity, postsynaptic AMPAR content, and mEPSC and EPSC magnitude (mimicking LTP), all of which were blocked by Myr-aPKC-PS and PKCl KD. PI3K activation also increased phosphorylation of the AMPAR GluA1 subunit on its PKC site S818. Phosphorylation of S818 by PKC is important for LTP under certain (Boehm et al, 2006) but not all conditions (Granger et al, 2013). It is possible that S818 phosphorylation plays a more important role in postsynaptic targeting of homomeric AMPAR that are formed by four GluA1 subunits rather than that of the more prevalent