# Voltage-gated calcium channels as target for anesthetics

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2022 · $489,825

## Abstract

One of the remaining fundamental challenges we face in pharmacology is deciphering the mechanisms of
action of general anesthetics (GAs). A complete anesthetic state involves loss of consciousness (hypnosis)
and movement (immobilization), as well as loss of pain sensation (analgesia) and recollection of the event
(amnesia). It is believed that GAs act through the multiple but specific proteins on neuronal membrane and
different ligand-gated and voltage-gated ion channels have received a significant consideration. One of
the compelling reasons to study voltage-gated calcium channels (VGCCs) in the mechanisms of anesthetic
actions is that these channels are essential in regulation of synaptic transmission and excitability in the
neuronal sleep pathway (e.g. thalamus) and in the brain regions involved in learning/memory (e.g. hippo-
campal formation). Importantly, our previous studies have established that low-voltage-activated subtype
of VGCCs or T-type calcium channels (T-channels) are inhibited by different classes of GAs within the
clinically relevant concentration range. For the past two decades our work has established the role of the
family of T-type VGCCs in acute and chronic pain processing, including post-surgical pain. However the
role of VGCCs in the mechanisms of GA-induced hypnosis and amnesia remains elusive. Furthermore,
despite substantial progress that has been made in the last two decades towards our understanding of
how GAs act at the molecular level, much less is known about how GAs cause hypnosis and memory
deficit at the level of intact neuronal networks. Hence, this proposal aims to elucidate the contribution of
specific subtypes of T-channels to anesthetic effects in the thalamocortical (Research area 1) and hippo-
campal circuitry (Research area 2). We will take advantage of mouse genetics, selective knock-down of
different T-channel isoforms ex vivo and in vivo electrophysiology, optical recordings, as well as a battery
of behavioral tests to address these key challenges. Our proposed work has the potential to overturn ex-
isting dogma about anesthetic mechanisms and to shift the focus to underappreciated targets, such as
neuronal T-channels. We posit that understanding the neurophysiological mechanisms of action of GAs
that target T-channels may be used as a starting point to develop novel and potentially safer approaches
and practices in clinical anesthesia. MIRA mechanism is well suited to achieve our stated goals because
of flexibility to pursue new avenues within the research area of interest to NIGMS. Consistent productivity
of our lab and our ability to collaborate with others in the field of anesthetic pharmacology strongly suggest
that our approach will be fruitful. The proposed work is innovative in that new mechanisms of useful clinical
effects of general anesthetics such as loss of consciousness and amnesia will be characterized. It is med-
ically significant because it describes the importance of drugs that ta...

## Key facts

- **NIH application ID:** 10402374
- **Project number:** 5R35GM141802-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Slobodan M. Todorovic
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $489,825
- **Award type:** 5
- **Project period:** 2021-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10402374

## Citation

> US National Institutes of Health, RePORTER application 10402374, Voltage-gated calcium channels as target for anesthetics (5R35GM141802-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10402374. Licensed CC0.

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