Related Experiment Video

Updated: Aug 11, 2026

Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
09:16

Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes

Published on: June 3, 2018

A beta1-adrenergic receptor CaM kinase II-dependent pathway mediates cardiac myocyte fetal gene induction

Carmen C Sucharov1, Peter D Mariner, Karin R Nunley

  • 1University of Colorado Cardiovascular Institute, Campus Box B130, UCHSC, Denver, CO 80262, USA.

American Journal of Physiology. Heart and Circulatory Physiology
|February 28, 2006
PubMed

Insights

Chronic beta-adrenergic receptor activation in heart failure triggers a detrimental fetal gene program. This response is specifically mediated by beta1-AR, involving Ca2+/calmodulin-dependent protein kinase (CaMK) and L-type Ca2+ channels, not cAMP.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cardiac Pharmacology

Background:

  • Beta-adrenergic signaling is crucial in dilated cardiomyopathies.
  • Chronic beta-receptor activation during cardiac stress negatively impacts the failing heart via gene expression changes.

Purpose of the Study:

  • To investigate the specific beta-adrenergic receptor (beta-AR) subtypes and signaling pathways mediating the fetal gene response in neonatal rat ventricular myocytes.
  • To elucidate the role of cAMP, protein kinase A, Ca2+/calmodulin-dependent protein kinase (CaMK), and L-type Ca2+ channels in this process.

Main Methods:

  • Stimulation of neonatal rat ventricular myocytes with isoproterenol to activate beta-ARs.
  • Analysis of human cardiac fetal and adult gene promoter activities (alpha-myosin heavy chain [alpha-MyHC], atrial natriuretic peptide [ANP], beta-MyHC).
  • Measurement of endogenous gene expression via mRNA levels; investigation of signaling pathway involvement (cAMP, PKA, CaMK, L-type Ca2+ channels).

Main Results:

  • Isoproterenol induced a fetal gene program, repressing alpha-MyHC and activating ANP and beta-MyHC promoters, correlating with mRNA expression changes.
  • The response was specifically mediated by beta1-AR, independent of beta2-AR and alpha1-AR stimulation.
  • The fetal gene response was independent of cAMP and protein kinase A but blocked by CaMK inhibition and dependent on L-type Ca2+ channel activation.

Conclusions:

  • In neonatal rat cardiac myocytes, beta1-AR activation induces a fetal gene program through cAMP-independent pathways involving CaMK.
  • Mobilization of Ca2+ stores and activation of L-type Ca2+ channels are critical for this beta1-AR-mediated fetal gene induction.

More Related Videos

Modified Mouse Embryonic Stem Cell based Assay for Quantifying Cardiogenic Induction Efficiency08:08

Modified Mouse Embryonic Stem Cell based Assay for Quantifying Cardiogenic Induction Efficiency

Published on: April 22, 2011

Assessing Cardiomyocyte Subtypes Following Transcription Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts09:29

Assessing Cardiomyocyte Subtypes Following Transcription Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts

Published on: March 22, 2017

Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
TGF - β Signaling Pathway01:16

TGF - β Signaling Pathway

The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...
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,...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
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,...