# Signaling Scaffolds for Specificity in Neuromodulator Action

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $384,198

## Abstract

Abstract
b2-adrenoceptor signaling is critical for adrenergic regulation of synaptic plasticity and neurodegeneration, and
has been proposed to have therapeutic potentials for Alzheimer’s and Parkinson’s diseases. However, b-
adrenoceptors (b-ARs) exhibit highly complicated pharmaceutical effects. This is exemplified by clinical results,
in which b-AR drugs modulate receptor paralogs in different organs to elicit both therapeutic and clinically
harmful effects at the same time. We aim to understand the signaling specificity of b2-adrenoceptors (b2-ARs),
mechanisms through which they are selectively coupled to different intracellular signaling proteins and
molecular effectors under different conditions. Our published and preliminary results manifest the signaling
scaffold, synapse-associated protein of 97 kDa (SAP97) as an orchestrator of b2-AR signaling in hippocampal
neurons. Specifically, the b-isoform of SAP97 (S97b) tethers b2-ARs and the effector voltage-gated potassium
channel subunit Kv1.1 together to transduce activation of b2-AR signaling into inhibition of Kv1.1 and its removal
from the dendrite surface (collectively referred to as Kv1.1 inhibition). Consequently, b2-AR-induced Kv1.1
inhibition increases dendritic excitability and lowers the induction threshold for long-term synaptic potentiation.
Given b2-AR-signaling also regulates the phosphorylation of the AMPA receptor subunit GluA1, but through a
different signaling scaffold, we hypothesize that signaling scaffolds mediate the signaling specificity and the
interactions can be used as specific pharmacological targets. In this proposal, using the S97b/b2-AR/Kv1.1
complex as an exemplary model, we aim to gain mechanistic insights into a) how the diverse b2-AR signaling
events are specifically regulated; b), what the molecular components of the S97b/b2-AR/Kv1.1 complex are to
achieve signaling specificity; and c) what are the behavioral correlates of the S97b/b2-AR/Kv1.1 signaling pathway
in mice. Importantly, in SAP97-lacking neurons, the signaling pathway governing b2-AR dependent dendritic
excitability is impaired with a ~100% penetrance, allowing an analysis with minimal confounding effects of
functional redundancy. The outcomes of our proposed experiments will provide a set of mechanistically clear
drug targets for treating psychiatric, neurological, immunological or cardiovascular disorders, and perhaps more
importantly lead to a novel and generalizable molecular scheme, through which G-protein-coupled receptors
achieve biased and selective regulations of specific effector proteins to modulate synaptic transmission and
plasticity.

## Key facts

- **NIH application ID:** 9875488
- **Project number:** 5R01NS107604-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Oliver Schlueter
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $384,198
- **Award type:** 5
- **Project period:** 2019-03-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875488

## Citation

> US National Institutes of Health, RePORTER application 9875488, Signaling Scaffolds for Specificity in Neuromodulator Action (5R01NS107604-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9875488. Licensed CC0.

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