Evolution of glutamatergic signaling and synapses

Leonid L Moroz; Mikhail A Nikitin; Pavlin G Poličar; Andrea B Kohn; Daria Y Romanova

doi:10.1016/j.neuropharm.2021.108740

Evolution of glutamatergic signaling and synapses

Neuropharmacology. 2021 Nov 1:199:108740. doi: 10.1016/j.neuropharm.2021.108740. Epub 2021 Jul 31.

Authors

Leonid L Moroz¹, Mikhail A Nikitin², Pavlin G Poličar³, Andrea B Kohn⁴, Daria Y Romanova⁵

Affiliations

¹ Whitney Laboratory for Marine Biosciences, University of Florida, St. Augustine, FL, 32080, USA; Departments of Neuroscience and McKnight Brain Institute, University of Florida, Gainesville, FL, 32610, USA. Electronic address: moroz@whitney.ufl.edu.
² Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow, 119991, Russia; Kharkevich Institute for Information Transmission Problems, Russian Academy of Sciences, Moscow, 127994, Russia.
³ Whitney Laboratory for Marine Biosciences, University of Florida, St. Augustine, FL, 32080, USA; Faculty of Computer and Information Science, University of Ljubljana, SI-1000, Ljubljana, Slovenia.
⁴ Whitney Laboratory for Marine Biosciences, University of Florida, St. Augustine, FL, 32080, USA.
⁵ Cellular Neurobiology of Learning Lab, Institute of Higher Nervous Activity and Neurophysiology, Moscow, 117485, Russia. Electronic address: darjaromanova@gmail.com.

Abstract

Glutamate (Glu) is the primary excitatory transmitter in the mammalian brain. But, we know little about the evolutionary history of this adaptation, including the selection of l-glutamate as a signaling molecule in the first place. Here, we used comparative metabolomics and genomic data to reconstruct the genealogy of glutamatergic signaling. The origin of Glu-mediated communications might be traced to primordial nitrogen and carbon metabolic pathways. The versatile chemistry of L-Glu placed this molecule at the crossroad of cellular biochemistry as one of the most abundant metabolites. From there, innovations multiplied. Many stress factors or injuries could increase extracellular glutamate concentration, which led to the development of modular molecular systems for its rapid sensing in bacteria and archaea. More than 20 evolutionarily distinct families of ionotropic glutamate receptors (iGluRs) have been identified in eukaryotes. The domain compositions of iGluRs correlate with the origins of multicellularity in eukaryotes. Although L-Glu was recruited as a neuro-muscular transmitter in the early-branching metazoans, it was predominantly a non-neuronal messenger, with a possibility that glutamatergic synapses evolved more than once. Furthermore, the molecular secretory complexity of glutamatergic synapses in invertebrates (e.g., Aplysia) can exceed their vertebrate counterparts. Comparative genomics also revealed 15+ subfamilies of iGluRs across Metazoa. However, most of this ancestral diversity had been lost in the vertebrate lineage, preserving AMPA, Kainate, Delta, and NMDA receptors. The widespread expansion of glutamate synapses in the cortical areas might be associated with the enhanced metabolic demands of the complex brain and compartmentalization of Glu signaling within modular neuronal ensembles.

Keywords: Algae; Aplysia; Aspartate; Cnidaria; Ctenophores; Eukaryotes; GABA; Glutamate receptors; Glutamine; Nervous system evolution; Neurotransmitters; Placozoa; Stress; Synapse; Trichoplax; Vesicular glutamate transporters; scRNA-seq.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Review

MeSH terms

Animals
Biological Evolution*
Glutamic Acid / physiology*
Receptors, Glutamate / physiology*
Signal Transduction / physiology*
Synapses / physiology*

Substances

Receptors, Glutamate
Glutamic Acid

Grants and funding

R01 NS114491/NS/NINDS NIH HHS/United States