Biology subjects

Zakon, H. H.

Publications and source records attributed to Zakon, H. H..

3 recordsLinked to original sources

bioRxiv2026

An atomic interaction conserved for over 600 million years gates inhibitory neurotransmission

Pentameric ligand-gated ion channels (pLGICs) mediate fast inhibitory neurotransmission critical for neuronal network stability. A tyrosine residue in the M2-M3 linker of inhibitory pLGICs, conserved for over 600 million years, is positioned where it could hydrogen bond (H-bond) to the backbone of the neighboring Cys-loop. Given the pathogenic effects of variants of this tyrosine, we hypothesized that this H-bond stabilizes extracellular-to-transmembrane domain coupling essential for channel gating. To test this hypothesis, we used site-directed mutagenesis, noncanonical amino acid incorporation, and electrophysiological recordings in Xenopus laevis oocytes to disrupt this hydrogen bond in GABAA and glycine receptors. Loss of this interaction via tyrosine substitutions or backbone amide modifications that ablate the acceptor or donor, respectively, markedly decrease agonist sensitivity and maximal channel activation, with effects localized to specific subunits. Molecular dynamics simulations support a role for this H-bond in channel gating. These findings reveal a critical atomic interaction underlying a shared mechanism for inhibitory receptor gating and provide a mechanistic explanation for disease-associated mutations linked to epilepsy, neurodevelopmental disability, and hyperekplexia.

biophysics↗

bioRxiv2023

A potential cost of evolving epibatidine resistance in poison frogs

BackgroundSome poison arrow frogs sequester the toxin epibatidine as a defense against predators. We previously identified a single amino acid substitution (S108C) at a highly conserved site in a neuronal nicotinic acetylcholine receptor (nAChR) {beta}2 subunit that prevents epibatidine from binding to this receptor. When placed in a homologous mammalian nAChR this substitution minimized epibatidine binding but also perturbed acetylcholine binding, a clear cost. However, in the nAChRs of poison arrow frogs, this substitution appeared to have no detrimental effect on acetylcholine binding and, thus, appeared cost-free. ResultsThe introduction of S108C into the 4{beta}2 nAChRs of non-dendrobatid frogs also does not affect ACh sensitivity, when these receptors are expressed in Xenopus laevis oocytes. However, 4{beta}2 nAChRs with C108 had a decreased magnitude of neurotransmitter-induced currents in all species tested (Epipedobates anthonyi, non-dendrobatid frogs, as well as human), compared with 4{beta}2 nAChRs with the conserved S108. Immunolabeling of frog or human 4{beta}2 nAChRs in the plasma membrane using radiolabeled antibody against the {beta}2 nAChR subunit shows that C108 significantly decreased the number of cell-surface 4{beta}2 nAChRs, compared with S108. ConclusionsWhile S108C protects these species against sequestered epibatidine, it incurs a potential physiological cost of disrupted 4{beta}2 nAChR function. These results may explain the high conservation of a serine at this site in vertebrates, as well as provide an example of a tradeoff between beneficial and deleterious effects of an evolutionary change. They also provide important clues for future work on assembly and trafficking of this important neurotransmitter receptor.

evolutionary biology↗

bioRxiv2017

Evolution of Animal Neural Systems

Nervous systems are one of the most spectacular products of evolution. Their provenance and evolution have been an area of interest and often intense debate since the late 19th century. The genomics era has provided researchers with a new set of tools with which to study the early evolution of neurons, and recent progress on the molecular evolution of the first neurons has been both exciting and frustrating. It has become increasingly obvious that genomic data is often insufficient to reconstruct complex phenotypes in deep evolutionary time. We review this recent progress and its attendant challenges, and suggest ways forward.

evolutionary biology↗