Hou et al. describe how neurons activate the protein phosphatase PP1 in response to synaptic stimulation.
PP1 is a key regulator of synaptic plasticity, the phenomenon in which neurons modulate the strength of their synaptic connections in order to store memories. PP1 promotes long-term depression, for example, reducing the function of active synapses by dephosphorylating a number of synaptic and nuclear substrates. But how PP1 is activated during long-term depression is unclear.
PP1 is inhibited by the phosphorylation of a threonine residue in the protein’s C terminus. Hou et al. found that this phosphorylation was reduced in neurons stimulated by the neurotransmitter NMDA. The phosphatase calcineurin and the regulatory protein inhibitor-1 have been proposed to control PP1 activity, but inhibiting these proteins had no effect on PP1 phosphorylation, at least in cortical neurons. Instead, the researchers discovered that the neuron-specific cyclin-dependent kinase Cdk5 phosphorylates PP1’s C terminus. NMDA stimulation induced the degradation of Cdk5’s activator p35, limiting the kinase’s activity so that PP1 was able to dephosphorylate and activate itself.
NMDA also triggered the dephosphorylation of a phosphatase regulator called inhibitor-2, boosting the protein’s association with PP1. Surprisingly, knocking down inhibitor-2 enhanced the inhibitory phosphorylation of PP1 and prevented the induction of long-term depression. This suggests that, despite its name, inhibitor-2 may promote PP1 activity in neurons. Senior author Houhui Xia now wants to examine the effect of depleting inhibitor-2 in vivo and to determine how the protein affects PP1’s activity toward different neuronal substrates.
Text by Ben Short