# Alpha2delta-mediated control of neuronal signaling

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $362,785

## Abstract

PROJECT SUMMARY
Intracellular calcium drives neuronal signaling and excitability, and appropriate spatial and temporal control
of neuronal calcium signals are required to prevent dysregulated control of brain activity, which can lead to
epileptic seizures. One of the primary sources of calcium in neurons is entry via voltage-gated calcium channels
on the cell membrane, which is then coupled to various effector mechanisms through co-localization of
channels and calcium-responsive proteins within the neuron. Two specific, but distinct, calcium-dependent
processes critical for maintaining brain homeostasis involve retrograde endocannabinoid signaling and the
action potential afterhyperpolarization. Endocannabinoids are produced postsynaptically by neurons in a
calcium-dependent manner, and then diffuse to presynaptic terminals where they bind to CB1 receptors and
powerfully inhibit vesicle release at numerous synapses. Separately, voltage-dependent calcium entry activates
nearby coupled calcium-dependent potassium channels, mediating the action-potential afterhyperpolarization
which accelerates cell repolarization and controls neuronal firing rates. For each of these phenomena, tight
functional coupling of calcium entry to these disparate effectors is critical in maintaining brain function.
While the specific cellular mechanisms responsible for controlling the appropriate localization of voltage-gated
calcium channels remain largely unknown, our preliminary data indicate a critical role for the alpha2delta
proteins in the functional coupling of calcium entry to effectors. These auxiliary calcium channel subunits help
traffic voltage-gated calcium channels to the neuronal surface membrane, but have otherwise remained
enigmatic despite clear association with neurologic diseases in humans and mice. We hypothesize that the
alpha2delta proteins are critical mediators of functional coupling between calcium entry and calcium-
dependent signaling throughout the brain. We propose to use genetically modified mice and
electrophysiological assays to define the roles of alpha2delta isoforms in 1) calcium-dependent retrograde
signaling from cerebellar Purkinje cells to their various synaptic inputs, 2) the control of excitability and
endocannabinoid signaling in the hippocampus, and 3) the molecular mechanisms underlying these
phenomena using molecular replacement strategies. Together, these experiments will lead to a greatly
enhanced appreciation of the function of this important class of calcium channel subunits, which we believe
can be leveraged to improve our ability to control runaway excitability in the brain in conditions such as
epileptic seizures.

## Key facts

- **NIH application ID:** 10418233
- **Project number:** 1R01NS126247-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Eric Schnell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $362,785
- **Award type:** 1
- **Project period:** 2022-03-15 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10418233

## Citation

> US National Institutes of Health, RePORTER application 10418233, Alpha2delta-mediated control of neuronal signaling (1R01NS126247-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10418233. Licensed CC0.

---

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