# Engineering Nanobodies To Study Beta Subunit-Specific Voltage-Gated Calcium Channel Complexes in Pancreatic Beta Cells

> **NIH NIH F31** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $45,520

## Abstract

PROJECT SUMMARY
 Diabetes is a growing pandemic that is characterized by insufficiency of insulin, a key hormone of glucose
maintenance. Ca2+ influx through voltage-gated calcium channels (VGCCs) is necessary for glucose-stimulated
insulin secretion in pancreatic β-cells (PβCs), and has also been implicated in maintaining PβC identity, an
important regulatory point in diabetes progression. VGCCs are thus a potential locus for both PβC-dependent
pathophysiology and therapy. These channels are multi-subunit complexes comprised minimally of pore-forming
α1 subunits assembled with auxiliary (β, α2δ,and γ) proteins. In heterologous cells, CaVβ subunits (β1-β4) are
powerful regulators of VGCCs by controlling α1 subunit trafficking and tuning channel gating. A central
unresolved question is: how does Ca2+ influx via VGCCs give rise to divergent functions in PβCs such as insulin
secretion and excitation-transcription coupling? It is likely that differential sorting of VGCCs into spatially distinct
macromolecular complexes is a key underlying principle that enables such functional diversification of VGCC
Ca2+ signals. PβCs express multiple CaVα1 and β subunits− the precise functional roles of distinct CaVβs in PβC
physiology and pathophysiology are unclear. Nevertheless, CaVβs are downregulated in rodent models of
diabetes, and knockout models suggest they play a role in glucose homeostasis. I hypothesize that in PβCs
distinct CaVβs are instrumental in organizing VGCCs into discrete macromolecular complexes with specialized
functions. A significant barrier in our capacity to rigorously assess the functional roles of CaVβ molecular diversity
in excitable cells, including PβCs, is the inability to inhibit VGCCs based on the identity of their resident CaVβ.
Here, I propose to develop novel genetically-encoded CaV channel blockers that enable inhibition of
CaVβ-specific VGCC complexes, and apply them to decipher signaling functions of CaVβs in PβCs. The
approach exploits a bioengineering method to generate genetically-encoded VGCC inhibitors termed Channel
Inactivation by Membrane-tethering of an Associated Protein (ChIMP) pioneered by our lab. In this proposal, I
combine development of Cavβ isoform-selective nanobodies with molecular biology, electrophysiology, flow
cytometry, fluorescence resonance energy transfer (FRET), ion channel engineering, and biochemistry to
address two specific aims. First, I will develop and engineer nanobodies to selectively inhibit VGCCs on the basis
of their resident CaVβ. In my second aim I will elucidate the functions of CaVβ specific VGCC complexes in
pancreatic β-cells.

## Key facts

- **NIH application ID:** 9963251
- **Project number:** 5F31DK118866-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Travis James Morgenstern
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963251

## Citation

> US National Institutes of Health, RePORTER application 9963251, Engineering Nanobodies To Study Beta Subunit-Specific Voltage-Gated Calcium Channel Complexes in Pancreatic Beta Cells (5F31DK118866-03). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9963251. Licensed CC0.

---

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