# Optical control of neuromodulatory GPCRs

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $3,263,925

## Abstract

SUMMARY/ABSTRACT
A major goal of neuroscience is to understand how neuromodulatory systems regulate core processes of brain
and behavior, from motor function and learning to reward, aversion, attention, and sleep. These systems go
awry in schizophrenia and disorders of mood, motor control and cognition. Treatment for these conditions often
turns to pharmacological manipulation of neuromodulators and their receptors. Understanding of
neuromodulatory circuits has advanced considerably thanks to optogenetics and chemogenetics. But
neuromodulation is difficult to crack. A major obstacle is that a single neuromodulator may play many diverse
roles because it has multiple receptors, with different functions in different cell locations and different cells
within a circuit. Unfortunately, drugs and genetic manipulations cannot typically be targeted or controlled with
sufficient spatio-temporal precision to unravel these different functions. We are developing two approaches
that provide the needed precision by controlling native, full-length neuromodulatory receptors with
photoswitchable tethered ligands (PTLs). Preliminary Iwork demonstrates feasibility of both approaches as
applied to two core neuromodulatory receptor families: metabotropic glutamate receptors (mGluRs) and
dopamine receptors (DARs). In this proposal, we optimize and expands an approach in which we directly
attach PTLs to a specific receptor subtype and develop a new approach that does not touch those receptors,
but deliver the PTL to them on a membrane anchor. Because the membrane anchor can be targeted to specific
locations within the cell, it can selectively control receptors only at that location, and it can use either broad
ligands (which hit all local receptors of that type) or highly selective ligands (to control only one subtype at a
time). The tools will be demonstrated in mice and provided to the community as gene delivery vectors, PTLs
and transgenic animal lines.

## Key facts

- **NIH application ID:** 10012228
- **Project number:** 1RF1MH123246-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Ehud Isacoff
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $3,263,925
- **Award type:** 1
- **Project period:** 2020-08-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10012228

## Citation

> US National Institutes of Health, RePORTER application 10012228, Optical control of neuromodulatory GPCRs (1RF1MH123246-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10012228. Licensed CC0.

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