# AKAP-dependent regulation of Cardiac SR Ca handling

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2020 · $496,002

## Abstract

Project Summary/ Abstract
Beta-adrenergic receptor (β-AR) activation affects cardiac excitation-contraction coupling (ECC)
through coordinated increases in sarcoplasmic reticulum (SR) Ca uptake by SERCA and
release via ryanodine receptor (RyR) channels. Reduced SR Ca uptake and sensitized SR Ca
release contribute to reduced SR Ca content in heart failure (HF), and are key therapeutic
targets in HF. However, there are key gaps in our fundamental understanding of ß-AR
regulation of these SR Ca handling processes in cardiac myocytes, which our team is well-
poised to address. SR Ca uptake is basally inhibited by phospholamban (PLB), an effect that is
relieved by PLB phosphorylation by PKA. A quantitative mechanistic question is how a small
number of PKA molecules in the cell can rapidly phosphorylate the far more numerous (>200-
fold) and widely distributed PLB, to uniformly accelerate [Ca]i decline and SR Ca load 
upon ß-AR activation. It is unlikely that dedicated anchoring of PKA near each small cluster of PLB
molecules would suffice from a quantitative standpoint. New data suggest that PLB
phosphorylation can decrease PLB affinity of A-kinase anchoring protein, AKAP7. We will test
the hypothesis that upon ß-AR activation, the AKAP7 that is bound to un-phosphorylated PLB
phosphorylates nearby PLB molecules, but then detaches, only to bind again quickly to a
neighboring area of unphosphorylated PLBs (i.e. “hovering” along the SR, phosphorylating
sequential PLB clusters). This new paradigm, which differs from the standard, accepted 1:1
relationship between other AKAPs and their targets, may be critical to rapid adrenergic fight-or-
flight response. Aim 1 will test how AKAP7 mobility is influenced by PLB binding and
phosphorylation to expedite adrenergic cardiac lusitropy. Aim 2 will test consequences of
disrupting the AKAP7-PLB interaction with respect to spatiotemporal spread of SERCA
activation in single myocytes. Aim 3 will test for AKAP7-CaMKII interaction and its potential
effects on PLB & RyR. This work will provide novel and clear mechanistic data regarding the
fundamental mechanism of rapid synchronous adrenergic activation throughout the myocyte
and heart. This may present a novel type of AKAP function, where targeted translocation of the
AKAP amplifies signaling to very large numbers of target sites.

## Key facts

- **NIH application ID:** 9910438
- **Project number:** 5R01HL133832-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Donald M Bers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $496,002
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9910438

## Citation

> US National Institutes of Health, RePORTER application 9910438, AKAP-dependent regulation of Cardiac SR Ca handling (5R01HL133832-04). Retrieved via AI Analytics 2026-06-16 from https://api.ai-analytics.org/grant/nih/9910438. Licensed CC0.

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