The origin and diversity of PICK1 palmitoylation in the Eutheria

Abstract

Glutamate is the major excitatory neurotransmitter in the vertebrate central nervous system. AMPA-type ionotoropic glutamate receptors (AMPA receptors) are responsible for the glutamate-mediated postsynaptic excitation of neurons. The trafficking of AMPA receptors into and out of synapses is highly dynamic and is regulated by various AMPA receptor-interacting proteins that bind to the cytoplasmic tail of the receptors. This process is regulated by palmitoylation of AMPA receptors and PDZ domain-containing AMPA receptor-interacting proteins, such as PSD-95 and GRIP1b. Post-translational protein palmitoylation is the only reversible covalent attachment of lipid to protein. Protein interacting with C-kinase 1 (PICK1) is an AMPA receptor-interacting protein, associating directly with the C-termini of AMPA receptors through its PDZ domain. PICK1 has been shown to regulate the surface expression, trafficking, and synaptic targeting of AMPA receptors in several forms of synaptic plasticity. Our previous study revealed that post-translational protein palmitoylation of PICK1 C-terminus regulates PICK1-mediated internalization of AMPA receptors in mammalian neurons. In this report, I analyzed conservation and divergence of palmitoylation sites found in PICK1 orthologs. Analysis of databases revealed that the palmitoylation site of PICK1 has been broadly conserved during evolution in the eutherian (placental) lineage, whereas the corresponding sites are substituted in subclasses Prototheria (platypus) and Metatheria (Marsupialia) and exceptionally some species in Eutheria (Placentalia). This finding indicates that palmitoylation-dependent regulation mechanism of PICK1 was established much later than those of AMPA receptors and other PDZ domain-containing AMPA receptor-interacting proteins, which are completely conserved in all vertebrate species. PICK1-dependent dynamic trafficking of glutamatergic synapses made possible by this reversible palmitoylation of PICK1 C-terminus may be critical for the specific refined functions of complex placental nervous systems.