Frequency-dependent acceleration of relaxation in the heart depends on CaMKII, but not phospholamban

Related Experiment Video

Updated: Sep 29, 2026

Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling
08:29

Assessment of Myofilament Ca2+ Sensitivity Underlying Cardiac Excitation-contraction Coupling

Published on: August 1, 2016

Jaime DeSantiago1, Lars S Maier, Donald M Bers

  • 1Department of Physiology, Stritch School of Medicine, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA.

Journal of Molecular and Cellular Cardiology
|September 18, 2002
PubMed

Insights

Frequency-dependent acceleration of relaxation (FDAR) enhances ventricular filling at higher heart rates. This study shows FDAR primarily involves CaMKII-dependent SR Ca transport, independent of phospholamban.

Area of Science:

  • Cardiology
  • Molecular Physiology
  • Biophysics

Background:

  • Frequency-dependent acceleration of relaxation (FDAR) improves diastolic filling during increased heart rates.
  • The precise molecular mechanisms underlying FDAR remain incompletely understood.
  • FDAR is observable in intact cardiac tissues and isolated cardiac cells.

Purpose of the Study:

  • To investigate the role of Ca/calmodulin-dependent protein kinase II (CaMKII) in FDAR.
  • To determine if phospholamban is essential for FDAR.
  • To elucidate the contribution of sarcoplasmic reticulum (SR) Ca transport to FDAR.

Main Methods:

  • Experiments utilized isolated ventricular muscle and myocytes from wild-type and phospholamban knockout mice, as well as rat ventricular myocytes.
  • Measurements included isometric twitch force, unloaded shortening, and intracellular calcium transients.
  • CaMKII activity was inhibited using KN-93 and autocamtide-2 related inhibitory peptide (AIP) across a range of stimulation frequencies (0.2-8Hz).

Main Results:

  • FDAR of twitch force was observed in both wild-type and phospholamban knockout mouse muscles and was significantly reduced by KN-93.
  • In phospholamban knockout myocytes, FDAR of contractions correlated with FDAR of calcium transients, both inhibited by KN-93.
  • Autocamtide-2 related inhibitory peptide (AIP) also inhibited FDAR of contraction and calcium transients in rat ventricular myocytes.

Conclusions:

  • FDAR is primarily mediated by CaMKII-dependent stimulation of SR Ca transport.
  • Phospholamban is not required for the FDAR mechanism.
  • CaMKII plays a crucial role in regulating SR Ca handling to facilitate rapid relaxation.

Keywords:
Non-programmatic

More Related Videos

Optical Mapping of Intra-Sarcoplasmic Reticulum Ca2+ and Transmembrane Potential in the Langendorff-perfused Rabbit Heart09:26

Optical Mapping of Intra-Sarcoplasmic Reticulum Ca2+ and Transmembrane Potential in the Langendorff-perfused Rabbit Heart

Published on: September 10, 2015

Mechanical Control of Relaxation Using Intact Cardiac Trabeculae07:51

Mechanical Control of Relaxation Using Intact Cardiac Trabeculae

Published on: February 17, 2023

Related Concept Videos

Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
G-Protein Gated Ion Channels01:21

G-Protein Gated Ion Channels

GPCRs are primarily responsible for our sense of smell, taste, and vision.  The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory organs,...
Relaxation of Skeletal Muscles01:29

Relaxation of Skeletal Muscles

The period of muscle contraction primarily influences the duration of stimulation at the neuromuscular junction (NMJ), the presence of free calcium ions in the sarcoplasm, and the availability of energy or ATP to support contractions.
When an action potential reaches the axon terminal, it depolarizes the membrane and opens voltage-gated sodium channels. Sodium ions enter the cell, further depolarizing the presynaptic membrane. This depolarization causes voltage-gated calcium channels to open.
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
Smooth Muscle Contraction01:25

Smooth Muscle Contraction

Smooth muscle contraction is a complex process vital for various bodily functions, from maintaining blood vessel tension to facilitating the movement of food through the digestive tract. Unlike striated muscles, smooth muscle contraction begins more slowly and lasts longer.
The onset of contraction is triggered by an increase in calcium ions within the sarcoplasm, similar to the process in striated muscle. However, smooth muscles have a relatively smaller reservoir of the sarcoplasmic...
Feedback Regulation of Calcium Concentration01:27

Feedback Regulation of Calcium Concentration

Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...