PICK1 Mediates Synaptic Recruitment of AMPA Receptors at Neurexin-Induced Postsynaptic Sites

Abstract

In the CNS, synapse formation and maturation play crucial roles in the construction and consolidation of neuronal circuits. Neurexin and neuroligin localize on the opposite sides of synaptic membrane and interact with each other to promote the assembly and specialization of synapses. However, the excitatory synapses induced by the neurexin-neuroligin complex are initially immature synapses that lack AMPA receptors. Previously, PICK1 (protein interacting with C kinase 1) was shown to cluster and regulate the synaptic localization of AMPA receptors. Here, we report that during synaptogenesis induced by neurexin in cultured neurons from rat hippocampus, PICK1 recruited AMPA receptors to immature postsynaptic sites. This synaptic recruitment of AMPA receptors depended on the interaction between GluA2 and PICK1, and on the lipid-binding ability of PICK1, but not the interaction between PICK1 and neuroligin. Last, our results demonstrated that the recruitment of GluA2 to synapses could be prevented by ICA69 (islet cell autoantigen 69 kDa), a key binding partner of PICK1. Our study showed that PICK1, being negatively regulated by ICA69, could facilitate synapse maturation.

Syntabulin regulates the trafficking of PICK1-containing vesicles in neurons

“…Moreover, both PICK1-deficient Drosophila and mice display somatic growth retardation due to impaired biogenesis of growth hormone secretory vesicles 20 . Our previous studies in neurons also showed that PICK1 could maintain a synaptic pool of AMPA receptors that might exist in a clustered vesicle form 21 22 .…”

“…For example, in the case of AMPA receptors, PICK1 binds to the GluA2 subunit in a PDZ-dependent manner 1 2 , and the BAR domain of PICK1 binds to lipids and targets the proteins to synapses or dendritic shafts by forming distinct dimeric complexes 3 22 . As a result of this synergetic effect of the above mentioned two domains, PICK1 mediates the translocation of AMPA receptors into and out of synapses 21 22 .…”

The Extracellular-Regulated Kinase Effector Lk6 is Required for Glutamate Receptor Localization at the Drosophila Neuromuscular Junction

“… 79 CAM signaling is activated by binding to themselves, other CAMs, or the extracellular matrix and is important for synaptic plasticity and the localization of neurotransmitter receptors. 80 , 81 Attractive potential targets of Lk6 include the neurexin–neuroligin complex, which, at mammalian CNS synapses, recruits GluA2 to the synapse through interactions with PICK1 82 and has been shown to regulate GluRIIA localization in Drosophila embryos. 83 Lk6 may also regulate translation of cadherin–catenin complexes, which, in mammals, have been shown to enhance the surface localization of GluA2 84 and the kainate receptor subunit, GluK6.…”

Islet-cell autoantigen 69 mediates the antihyperalgesic effects of electroacupuncture on inflammatory pain by regulating spinal glutamate receptor subunit 2 phosphorylation through protein interacting with C-kinase 1 in mice

“…7,8 Recent studies showed that ICA69 could influence AMPA receptors, which mediate synaptic plasticity via interacting with PICK1. 38,43 Our previous investigation found that absence of ICA69 enhanced the long-lasting hyperalgesia induced by subcutaneous formalin injection into the mouse hind paw. Furthermore, ICA69 knockout (KO) led to increased GluR2 phosphorylation at Ser880 in SDH.…”