Abstract
Synaptic α‐amino‐3‐hydroxyl‐5‐methyl‐4‐isoxazole‐propionate (AMPA) receptors are essential mediators of neurotransmission in the central nervous system. Shisa9/cysteine‐knot AMPAR modulating protein 44 (CKAMP44) is a transmembrane protein recently found to be present in AMPA receptor‐associated protein complexes. Here, we show that the cytosolic tail of Shisa9/CKAMP44 interacts with multiple scaffold proteins that are important for regulating synaptic plasticity in central neurons. We focussed on the interaction with the scaffold protein PICK1, which facilitates the formation of a tripartite complex with the protein kinase C (PKC) and thereby regulates phosphorylation of Shisa9/CKAMP44 C‐terminal residues. This work has implications for our understanding of how PICK1 modulates AMPAR‐mediated transmission and plasticity and also highlights a novel function of PKC.
Highlights
Synaptic a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors are essential mediators of neurotransmission in the central nervous system
It has been shown that Shisa9 and Shisa6, 7 and 8 are Abbreviations AMPA, a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; CaMKII, Ca2+/calmodulin-dependent protein kinase II; CKAMP44, cysteine-knot AMPAR modulating protein 44; MAGI1, membrane-associated guanylate kinase inverted 1; membraneassociated guanylate kinase (MAGUK), membrane-associated guanylate kinase; neuronal protein interacting specifically with Tc10 (nPIST), neuronal protein interacting with Tc10; PDZ, PSD-95 Dlg1 and ZO-1; PICK1, protein interacting with C kinase 1; PKA, protein kinase A; PKC, protein kinase C; PMA, phorbol-12-myristate-13-acetate; PSD-95, postsynaptic density protein 95; SAP102, synapse-associated protein 102; TARP, transmembrane AMPAR regulatory protein; Y2H, yeast two-hybrid
We have identified several Shisa9/CKAMP44 binding proteins, including several scaffold molecules that play an established role in the regulation of cell–cell communication, for example PICK1 and the MAGUK family members PSD-95, SAP102 and MAGI1
Summary
Synaptic a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors are essential mediators of neurotransmission in the central nervous system. It has been shown that Shisa and Shisa and 8 are Abbreviations AMPA, a-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate; CaMKII, Ca2+/calmodulin-dependent protein kinase II; CKAMP44, cysteine-knot AMPAR modulating protein 44; MAGI1, membrane-associated guanylate kinase inverted 1; MAGUK, membrane-associated guanylate kinase; nPIST, neuronal protein interacting with Tc10; PDZ, PSD-95 Dlg and ZO-1; PICK1, protein interacting with C kinase 1; PKA, protein kinase A; PKC, protein kinase C; PMA, phorbol-12-myristate-13-acetate; PSD-95, postsynaptic density protein 95; SAP102, synapse-associated protein 102; TARP, transmembrane AMPAR regulatory protein; Y2H, yeast two-hybrid. In the light of these new studies, this subgroup of Shisa proteins is referred to as the CKAMP family, based on their common ability to modulate AMPAR synaptic transmission Another property that these CKAMP proteins share is the presence of a conserved C-terminal sequence typical for proteins that have been shown to bind a postsynaptic density protein 95 (PSD-95) Dlg and ZO-1 (PDZ) domain, the 80–90 AA structurally conserved motif originally identified for its presence in PSD-95, Dlg and ZO-1 proteins
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