# The Effect of Isoflurane on Axonal Endoplasmic Reticulum Ca2+ Dynamics in Hippocampal Neurons

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $45,520

## Abstract

Project Summary/Abstract
Volatile anesthetics are essential to modern medicine, but despite their widespread clinical use, their
precise cellular and molecular mechanisms of action remain unclear. Volatile anesthetics, such as
isoflurane, depress synaptic transmission with both pre- and post-synaptic effects including inhibition of
activity-dependent Ca2+ influx into the presynaptic nerve terminal. However, the principal presynaptic sites
of action upstream of Ca2+ entry are unknown. Axonal endoplasmic reticulum (ER) Ca2+ controls
presynaptic Ca2+ through ER Ca2+ sensing proteins, and decreased ER Ca2+ has been linked to a reduction
in presynaptic Ca2+ influx through these proteins. ER Ca2+ efflux and influx mechanisms are essential for
Ca2+ regulation and provide possible targets for anesthetic action. For example, in skeletal muscle,
mutations in sarcoplasmic reticulum (SR) Ca2+ efflux receptors: ryanodine receptors (RyR) result in patient
with episodes of malignant hyperthermia (MH) after treatment with volatile anesthetics. MH is a potentially
fatal pharmacogenetic disorder characterized by hyperthermia, tachycardia, muscle rigidity, and
hypermetabolism [1]. However, MH's effect on neurons is unknown. As my preliminary data show,
isoflurane decreases activity-dependent ER Ca2+ surges.
Isoflurane inhibits presynaptic Ca2+ entry and synaptic vesicle (SV) exocytosis, which I
hypothesize involves effects on ER Ca2+ efflux dynamics through ryanodine receptors (RyR). I will
address this hypothesis through the following specific aims: 1) Determine the effects of isoflurane on ER
Ca2+ efflux and influx pathways; 2) Determine the effect of isoflurane on ER Ca2+ in neurons from an MH
model mouse. Primary cultures of rat hippocampal neurons will be used to test isoflurane-induced
changes in ER Ca2+ concentration using fluorescent biosensors and pharmacological modulators of ER
Ca2+ regulators. Under the mentorship of Dr. Hugh C. Hemmings Jr. at Weill Cornell Medicine, I plan to
further our understanding of isoflurane's neuronal mechanisms of action. Successful completion of these
aims will reveal novel presynaptic mechanisms and aid in the development of more-selective anesthetics
decreasing patient risk as well as facilitate the improvement of MH patient outcomes.

## Key facts

- **NIH application ID:** 9933813
- **Project number:** 5F31GM133115-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Vanessa  Osman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933813

## Citation

> US National Institutes of Health, RePORTER application 9933813, The Effect of Isoflurane on Axonal Endoplasmic Reticulum Ca2+ Dynamics in Hippocampal Neurons (5F31GM133115-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933813. Licensed CC0.

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