# Structure and function of voltage-gated calcium channels

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $783,575

## Abstract

The long-term goals of this project are to develop a high-resolution understanding of voltage-gated calcium
channel (CaV) function and regulation. These molecular switches play pivotal roles in cardiac action potential
propagation, neurotransmitter release, muscle contraction, calcium-dependent gene-transcription, and synaptic
transmission. Calcium influx is a potent activator of intracellular signaling pathways but is toxic in excess. As a
result, its entry into cells is tightly regulated. CaVs are major sources of activity-dependent calcium influx and
possess a number of mechanisms that allow them to self-regulate. These mechanisms depend critically on
interactions of the pore-forming subunit with cytoplasmic proteins that regulate channel activity. Our studies
are aimed at understanding the molecular architecture that underlies CaV function and on developing novel
reagents that can control channel function. We are investigating the hypothesis that two principal CaV
inactivation mechanisms, calcium-dependent inactivation (CDI) and voltage-dependent inactivation (VDI)
center on changes in the region of the selectivity filter. This is a paradigm-shifting view, based on our recent
findings, that stands to align CaV inactivation mechanisms with a growing number of examples from other
voltage-gated ion channel (VGIC) superfamily members. Due to the extraordinary challenges in studying
mammalian membrane protein structure, part of our efforts focus on understanding basic structural mechanisms
that are shared between CaVs and their ancestors, bacterial voltage gated sodium channels (BacNaVs). Production
of multiprotein membrane proteins, such as CaVs, is a significant barrier to structural studies. To bridge this gap,
we direct efforts to develop systems for production of full-length CaV complexes. In parallel, we investigate the
how a novel class of reagents, anti-CaVβ subunit nanobodies, interact with CaVβ and modify channel function.
Knowledge of such interactions will inform studies of how these novel, genetically-encodable reagents can be
developed as versatile and selective agents to control CaV activity. Our studies integrate a multidisciplinary
effort that includes biochemical, biophysical, X-ray crystallographic, cryo-electronmicroscopy,
electrophysiological, and cell biology approaches. Because of their important role in human physiology, CaVs
are the targets for drugs with great utility for the treatment of cardiac arrhythmias, hypertension, congestive
heart failure, epilepsy, and chronic pain. Thus, understanding their structures and mechanisms of action in detail
should greatly assist the development of valuable therapeutic agents for a wide range of human cardiac and
neurological problems.

## Key facts

- **NIH application ID:** 9972679
- **Project number:** 2R01HL080050-14A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** DANIEL L MINOR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $783,575
- **Award type:** 2
- **Project period:** 2005-05-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972679

## Citation

> US National Institutes of Health, RePORTER application 9972679, Structure and function of voltage-gated calcium channels (2R01HL080050-14A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9972679. Licensed CC0.

---

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