# Novel mechanism on subpopulation-dependent biased GPCR signaling in neurons

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $276,320

## Abstract

Summary
 Adrenergic receptors (ARs) are a family of prototypical GPCRs linked to neuronal disorders, metabolic
syndrome, and cardiovascular diseases. In the CNS, norepinephrine (NE) regulates attention and alertness.
The β2AR is emerging as the prevalent postsynaptic NE effector at glutmatergic synapses, where it interacts
with AMPAR, NMDAR and L-type Ca2+ channel Cav1.2 to modulate neuronal excitability, synaptic plasticity,
and memory and learning. It is clinically relevant to understand NE-linked mental diseases such as
depression, attention deficit hyperactivity disorder (ADHD), anxiety disorders (e.g., posttraumatic stress
disorder, PTSD) and Alzheimer's disease. While β-blockers are used to treat a variety of peripheral
diseases including heart failure, hypertension, glaucoma, asthma, and COPD, their clinical utility is
hampered by the side effects including anxiety and depression. Recent explosion of crystallography study of
ligand-GPCR interactions, there is still limited understanding on how a specific ligand leads to pleotropic
cellular responses (including sides effects) of a GPCR. In this study, we hypothesize that a distinct
subpopulation of PKA-phosphorylated β2ARs control LTCC activation in hippocampal neurons, which can
be selectively activated by a set of biased ligands. We will test our hypothesis with following specific aims:
Aim 1 is to test the hypothesis that β2AR can exist in distinct functional subpopulations in a single
mammalian cell. We will use biochemical isolation/fractionation and super-resolution imaging to
characterize distinct subcellular distribution of PKA-pβ2AR and GRK-pβ2AR. Aim 2 is to test the hypothesis
that PKA-pβ2AR transduce biased signal through selectively modulation of ion channel activity at the
plasma membrane (PM). Aim 3 is to test the hypothesis that sympathomimetic β-blockers act as biased
ligands that selectively activate PKA-phosphorylated subpopulation of β2AR to activate ion channel at the
PM. If successful, these aims will reveal a platform to understand the biased signaling induced by two
distinct subpopulations of β2AR, and offering a new avenues for designing more efficacious β-AR drugs with
fewer side effects in clinical applications.

## Key facts

- **NIH application ID:** 9933016
- **Project number:** 5R01GM129376-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** YANG Kevin XIANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $276,320
- **Award type:** 5
- **Project period:** 2018-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933016

## Citation

> US National Institutes of Health, RePORTER application 9933016, Novel mechanism on subpopulation-dependent biased GPCR signaling in neurons (5R01GM129376-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9933016. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*