# Anesthetics' Effects on Physiological Responses Modulated by Peripheral GABAA Receptors

> **NIH NIH R35** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $405,000

## Abstract

Abstract
Millions of patients receive anesthetics every year to facilitate surgical and diagnostic procedures. While
anesthetics are remarkably successful in achieving their intended goals in the central nervous system of
unconsciousness, amnesia and analgesia, anesthesia is accompanied by a myriad of peripheral physiologic
changes (e.g. hypotension) that at times can be life-threatening. The majority of commonly used anesthetics
today augment GABAergic neurotransmission in the central nervous system leading to their desired effects. It
has long been assumed that the accompanying peripheral physiologic perturbations that occur, result from
alterations in neuronal outflow from the central to the peripheral nervous systems and in turn to the end organs.
However, it is now appreciated that many of these end organs themselves express functional GABAA receptors
and that many of the physiologic effects of GABAergic anesthetics may in fact be due to direct GABAA receptor
cell signaling in these peripheral organs and cells. There is a large gap in knowledge regarding the
understanding of how GABAergic anesthetics interact with peripheral GABAA receptors on end organs (e.g.
immune cells, smooth muscle) to modify their function. A more thorough mechanistic understanding of the direct
physiological effects of GABAergic anesthetics on peripheral GABAA receptors will not only mitigate the
potentially life-threatening effects of anesthetics on peripheral physiology (e.g. hypotension), but will allow
peripheral GABAA receptors to be therapeutic targets in diseases such as hypertension, bronchoconstriction and
immune dysfunction. However, therapeutic targeting of peripheral GABAA receptors would have to avoid the
central sedative effects modulated by central GABAA receptors. Our laboratory was the first to discover GABAA
receptors expressed on airway smooth muscle and we subsequently identified novel imidazobenzodiazepine
derivatives that were modified to selectively target GABAA receptors containing 4 or 5 subunits and limit their
penetration to the central nervous system. These were important discoveries since most peripheral GABAA
receptors contain either 4 or 5 subunits, while central GABAA receptors that modulate sedation primarily
contain 1 and 2 subunits. Subsequently, we have shown the expression and functional effects of GABAA
receptors on immune cells and vascular smooth muscle. We will leverage these discoveries in the current
program to better understand the physiologic effects of a classic GABAergic anesthetic (i.e. propofol) and these
novel 4 and 5 subunit-selective benzodiazepine ligands on CD4+ lymphocytes, vascular smooth muscle and
airway smooth muscle function using cellular, ex vivo tissue and in vivo models from human and rodent sources.
Our findings will transform the mechanistic understanding of the physiologic effects of anesthetics, but more
importantly, identify potential novel therapeutic targets in hypertension, bronchoconstri...

## Key facts

- **NIH application ID:** 10167398
- **Project number:** 1R35GM140880-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** CHARLES W EMALA
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,000
- **Award type:** 1
- **Project period:** 2021-05-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167398

## Citation

> US National Institutes of Health, RePORTER application 10167398, Anesthetics' Effects on Physiological Responses Modulated by Peripheral GABAA Receptors (1R35GM140880-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10167398. Licensed CC0.

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