# Synaptic Mechanisms of General Anesthetic Action

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $541,910

## Abstract

Abstract
Despite widespread clinical use, knowledge of the mechanisms of general anesthetics is insufficient to explain
how they produce amnesia, unconsciousness or immobilization (with increasing doses), the cardinal features
of general anesthesia. The long-term goal of this project is to define the synaptic mechanisms that underlie
the actions of general anesthetics on the CNS. Anesthetics have potent and specific effects on synaptic
transmission, including both presynaptic actions on the release of neurotransmitters and postsynaptic actions
on receptors and dendritic spines. The principal objective of this research proposal is to understand synapse-
specific presynaptic effects of volatile anesthetics which are poorly understood. Our central hypothesis is that
general anesthetics have synapse-specific mechanisms resulting in selective effects on presynaptic ion
channels and exocytosis. The rationale underlying this proposal is that understanding presynaptic anesthetic
actions relevant to their therapeutic (unconsciousness, amnesia, immobility) and toxic (neurotoxicity, cognitive
dysfunction, respiratory and cardiovascular depression) effects of anesthetics is essential for developing new
anesthetics with improved side-effect profiles and for optimizing current anesthetic techniques in increasingly
high-risk patients. Our proposal that volatile anesthetics have distinct effects on the release of various
neurotransmitters due to differential presynaptic expression of anesthetic-sensitive ion channels coupled to
transmitter release, in particular voltage-gated sodium and calcium channels, is innovative in approach and
employs recently developed techniques in neuroscience and structural biology. The central hypothesis will be
tested using an integrative and collaborative multidisciplinary approach by the following three specific aims
employing in vivo, cellular and molecular methods: 1) Identify nerve terminal-specific presynaptic mechanisms
that influence the sensitivity of synaptic vesicle exocytosis to volatile anesthetics to test the hypothesis that
volatile anesthetics differentially inhibit synaptic vesicle exocytosis by nerve terminal-specific mechanisms
resulting from heterogeneous presynaptic ion channel expression; 2) Determine the effects of volatile
anesthetics on neuronal intracellular Ca2+ regulation and its impact on synaptic vesicle exocytosis to test the
hypothesis that volatile anesthetic effects on intracellular Ca2+ dynamics influence synaptic vesicle exocytosis;
and 3) Identify volatile anesthetic binding sites on voltage-gated sodium channels using the bacterial
homologue NavMs to test the hypothesis that volatile anesthetic inhibition involves direct interactions. The
research is significant in applying multidisciplinary and complementary electrophysiological, biophysical, and
imaging approaches involving a team of expert collaborators. The expected outcome is a molecular
understanding of synaptic anesthetic mechanisms under...

## Key facts

- **NIH application ID:** 10052822
- **Project number:** 2R01GM058055-21
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** HUGH C HEMMINGS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $541,910
- **Award type:** 2
- **Project period:** 1998-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052822

## Citation

> US National Institutes of Health, RePORTER application 10052822, Synaptic Mechanisms of General Anesthetic Action (2R01GM058055-21). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10052822. Licensed CC0.

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