# Regulation of Cav1.2 Trafficking by GJA1-20k and cBIN1

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $561,360

## Abstract

In normal hearts, the transverse tubules (t-tubules) concentrate L-type calcium channels
(LTCCs) to initiate the beat-to-beat intracellular calcium transients which contribute to the regulation of
cardiac contraction and relaxation. An altered calcium transient is a key pathophysiological sign of
failing heart. However, mechanisms of maintenance of LTCC expression at t-tubule microdomains for
optimal calcium-induced-calcium-release (CICR) remain poorly understood. Understanding the dynamic
regulation of calcium handling microdomains at t-tubules, and in particular LTCC regulation at the
microdomains, is needed to understand the pathophysiology of failing hearts and to identify new
pathways and molecules that can be targeted for heart failure therapy development.
 The overall objective of this MPI application is to further our mechanistic understanding of how
LTCC expression at t-tubule cBIN1-microdomains is maintained and why LTCC localization is altered in
heart failure. We will explore the central hypothesis that homeostatic LTCC expression at t-tubules is
highly dynamic and maintained by both internal delivery and external delivery. We expect that the
internal delivery is determined by intracellular actin reservoirs of LTCCs organized at Z-disks by a
newly identified actin nucleator GJA1-20k (Aim 1, RMS). We also expect that there is a local
extracellular reservoir of cBIN1 vesicles (Aim 2, TTH), which feed t-tubule cBIN1-microdomains from
other regions of the heart to modulate LTCC expression at t-tubule surfaces. In heart failure, both
sources are depleted yet could be exogenously restored.
 The resources of a membrane biology lab (TTH) and a trafficking lab focused on heart failure
progression (RMS) are combined in this application for the proposed research plan. The rationale that
underlies the proposed research is that LTCCs at t-tubule microdomains are dynamically regulated
from both inside and out, are reduced in heart failure, and can be restored presenting a novel therapy
for heart failure.
 The proposed research is innovative because it will identify new regulatory mechanisms of
remodeled myocardium during heart failure progression, and lead to the establishment of molecules
and pathways that can be targeted for therapy development. The proposal has a strong premise
because it is based on extensive published and preliminary data from successful in vitro cell-free
studies, intact cell line and primary cardiomyocyte studies, and successful genetic and in vivo animal
heart failure models. The significance is high because it will lead to development of new therapeutic
strategies that will allow preservation and restoration of efficient excitation-contraction coupling in
diseased hearts.

## Key facts

- **NIH application ID:** 10475207
- **Project number:** 5R01HL159983-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** TingTing Hong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $561,360
- **Award type:** 5
- **Project period:** 2021-09-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475207

## Citation

> US National Institutes of Health, RePORTER application 10475207, Regulation of Cav1.2 Trafficking by GJA1-20k and cBIN1 (5R01HL159983-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10475207. Licensed CC0.

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