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Lipid-stabilised asymmetric open state of the 5-HT3A serotonin receptor

ABSTRACT:

SUBMITTER: Mikhail Kudryashev

PROVIDER: EMPIAR-10381 | biostudies-other |

REPOSITORIES: biostudies-other

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Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers.

Zhang Yingyi Y Dijkman Patricia M PM Zou Rongfeng R Zandl-Lang Martina M Sanchez Ricardo M RM Eckhardt-Strelau Luise L Köfeler Harald H Vogel Horst H Yuan Shuguang S Kudryashev Mikhail M

Nature communications 20210216 1

Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A serotonin receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound s ...[more]

PMID: 33594077

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CryoEM SPA dataset of tetrameric forms of the serotonin-gated 5-HT3A receptor apo state

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Serotonin Receptor 5-HT3A Affects Development of Bladder Innervation and Urinary Bladder Function.

Project description:The autonomic and sensory nervous systems are required for proper function of all visceral organs, including the lower urinary tract (LUT). Despite the wide prevalence of bladder dysfunction, effective treatment options remain limited. Pelvic innervation regenerative strategies are promising, but surprisingly little is known about the molecular factors driving the development of bladder innervation. Given prior evidence that serotonin receptor 5-HT3A is expressed early in LUT development and is an important mediator of adult bladder function, we sought to determine if 5-HT3A is required for the development of autonomic innervation of the bladder. We found that 5-HT3A is expressed early in fetal mouse pelvic ganglia and is maintained through adulthood. Htr3a knockout male mice, but not females, exhibit increased urinary voiding frequency compared to wild type littermates. Analysis of LUT function via anesthetized cystometry revealed decreased voiding efficiency in male Htr3a mutants. Htr3a-/- mutant animals exhibit a transient disturbance of autonomic neuronal subtype markers (tyrosine hydroxylase and choline acetyl transferase) within the fetal pelvic ganglia, although the imbalance of neuronal subtype markers assayed is no longer apparent in adulthood. Loss of 5-HT3A activity results in a higher density of autonomic and sensory neuronal fibers supplying bladder smooth muscle in both fetal and adult mice. Collectively, our findings highlight 5-HT3A as a critical component in the autonomic control of micturition and identify a novel role for this serotonin receptor in peripheral nervous system development.

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Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers.

Project description:Pentameric ligand-gated ion channels (pLGICs) of the Cys-loop receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A serotonin receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT3R conformations in detergent, the lipid bilayer stabilises the receptor in a more tightly packed, 'coupled' state, involving a cluster of highly conserved residues. In consequence, the agonist-bound receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT3R by the membrane environment, and a model for asymmetric activation of the receptor.

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Project description: Not available

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