# Expanding the Pathogenic Mechanisms of Calmodulinopathies

> **NIH NIH R21** · UNIVERSITY OF MARYLAND BALTIMORE · 2022 · $231,750

## Abstract

Calmodulin (CaM) is a ubiquitous calcium sensor, vital to immune system, heart and brain function. Mutations
within CaM result in a set of disorders known as calmodulinopathies. Patients harboring these CaM mutations
suffer from life-threatening cardiac arrhythmias, which are often accompanied by neurodevelopmental delay or
other neurological dysfunction. While CaM has numerous potential targets which may be altered in
calmodulinopathies, voltage gated calcium channels (VGCCs) stand out as likely pathogenic elements. For
CaV1-2 channels, CaM is known to preassociate with the carboxy-tail of the channel. Upon binding Ca2+, this
resident CaM initiates either of two important forms of feedback regulation; Ca2+/CaM dependent inactivation
(CDI) or Ca2+/CaM dependent facilitation (CDF). Each of these forms of channel regulation can be independently
driven by a single lobe of CaM, with CaV1.2, CaV1.3 and CaV2.1 each strongly modulated by Ca2+ binding to the
C-lobe of CaM. As the majority of calmodulinopathy mutations have thus-far impacted the CaM C-lobe, this
lobe-specific regulation implies a large impact of calmodulinopathy mutations on the regulation of these three
channels. In fact, we have previously demonstrated that calmodulinopathy mutations are capable of disrupting
the CDI of CaV1.2 channels, resulting in the long-QT phenotype seen in patients6,7. However, the effect of CaM
mutations on VGCCs other than CaV1.2 has yet to be elucidated, nor have the mechanisms underlying the
neurological phenotypes of calmodulinopathy patients been explored. As CaV1-2 channels play critical roles in
neuronal excitability, excitation-transcription coupling, and neurotransmission, we propose that they are likely
contributors to the neuropathogenesis of calmodulinopathies. We will therefore undertake a biophysical study of
the impact of calmodulinopathy mutations across the CaV1-2 channel family and evaluate the impact of these
mutations on neuronal function. In particular, we hypothesize that CaM mutations which alter the Ca2+ binding
to the C-lobe of the protein will decrease CDI in CaV1.2 and CaV1.3, and disrupt CDF in CaV2.1. To evaluate the
functional impact of these mutations, we will generate induced pluripotent stem cell derived neurons (iPSC-neurons) from calmodulinopathy patients, and elucidate a cellular phenotype correlating with the neurological
deficits of calmodulinopathy patients. Thus, we will undertake one of the first studies aimed at understanding the
impact of calmodulinopathy mutations outside the heart, expanding our understanding of the pathogenic
mechanisms underlying this disorder.

## Key facts

- **NIH application ID:** 10426462
- **Project number:** 1R21NS127294-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Ivy E Dick
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $231,750
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10426462

## Citation

> US National Institutes of Health, RePORTER application 10426462, Expanding the Pathogenic Mechanisms of Calmodulinopathies (1R21NS127294-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10426462. Licensed CC0.

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