Smarter neuronal signaling complexes from existing components: How regulatory modifications were acquired during animal evolution

Abstract

Neurons of organisms with complex and flexible behavior, especially humans, must precisely control protein localization and activity to support higher brain functions such as learning and memory. In contrast, simpler organisms generally have simpler individual neurons, less complex nervous systems and display more limited behaviors. Strikingly, however, many key neuronal proteins are conserved between organisms that have very different degrees of behavioral complexity. Here we discuss a possible mechanism by which conserved neuronal proteins acquired new attributes that were crucial in the evolution of complexity of nervous system structure and function. Specifically, we hypothesize that vertebrate-specific post-translational palmitoylation sites and PDZ-binding protein-protein interaction motifs act as gain-of-function mutations, increasing the regulatory potential of conserved proteins without affecting their core functions. We further hypothesize that the additional regulation of neurotransmitter receptors and other membrane proteins made possible by these sites and motifs is critical for the function of complex nervous systems.

Ion channel regulation by protein S-acylation

“…Moreover, zDHHCs undergo autoacylation and contain predicted sites for other posttranslational modifications. Almost half of all mammalian zDHHCs contain a C-terminal PSD-95, Discs large, and ZO-1 (PDZ) domain binding motif, allowing them to assemble with various PDZ domain proteins that regulate ion channels (such as GRIP1b and PSD-95; Thomas and Hayashi, 2013). Other protein interaction domains are also observed in zDHHCs, such as ankyrin repeats in zDHHC17 and zDHHC13 (Greaves and Chamberlain, 2011).…”

“…The expansion of the number of zDHHCs in mammals (23 vs. 7 in yeast), together with increased prevalence of PDZ interaction motifs, likely represents evolutionary gain-of-function mechanisms to diversify zDHHC function (Thomas and Hayashi, 2013). Evolutionary gain of function is also seen in ion channel subunit orthologues through acquisition of S-acylated cysteine residues absent in orthologues lower in the phylogenetic tree (such as the transmembrane domain 4 [TM4] sites in GluA1–4 subunits of AMPA receptors [Thomas and Hayashi, 2013] and the sites in the alternatively spliced stress-regulated exon [STREX] insert in the C terminus of the BK channel [Tian et al, 2008]). Importantly, some zDHHCs may have additional roles beyond their acyltransferase function.…”

Comparative analysis of palmitoylation sites of serotonin (5‐HT) receptors in vertebrates

“…Previous researches have revealed that many other GPCRs are functionally regulated by their direct palmitoylation . So far, we have shown that palmitoylation sites of ionotropic glutamate receptors (iGluRs), the major excitatory neurotransmitter receptors in vertebrate central nervous system, and those of iGluRs‐binding proteins are extremely conserved in various species of whole vertebrate . Furthermore, palmitoylation sites of hyperpolarization‐activated cyclic nucleotide‐gated (HCN)‐2 channel and water channel aquaporin (AQP)‐4 are conserved across vertebrates.…”

Conservation and phylogenetic stepwise changes of aquaporin (AQP) 4 palmitoylation in vertebrate evolution

“…So far we have shown that palmitoylation sites of ionotropic glutamate receptors (iGluRs), the major excitatory neurotransmitter receptors in vertebrate central nervous system, and those of iGluRs-binding proteins are extremely conserved in various species of whole vertebrate [26][27][28] . Furthermore, palmitoylation sites of hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 channel is conserved in vertebrates [29] .…”