Related Experiment Video

Updated: Aug 9, 2026

Cardiac Stress Test Induced by Dobutamine and Monitored by Cardiac Catheterization in Mice
15:45

Cardiac Stress Test Induced by Dobutamine and Monitored by Cardiac Catheterization in Mice

Published on: February 10, 2013

Regulation of cardiac stress signaling by protein kinase d1

Brooke C Harrison1, Mi-Sung Kim, Eva van Rooij

  • 1Myogen, Inc., 7575 West 103rd Ave., Westminster, Colorado 80021, USA.

Molecular and Cellular Biology
|May 2, 2006
PubMed

Insights

Protein kinase D1 (PKD1) activates in heart muscle during pathological remodeling. It neutralizes Histone deacetylase 5 (HDAC5), a key factor in cardiac hypertrophy and fibrosis, thus controlling heart disease progression.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cell Signaling

Background:

  • Pathological cardiac remodeling, characterized by myocyte hypertrophy, death, and fibrosis, occurs in response to stresses like hypertension.
  • Histone deacetylase 5 (HDAC5) acts as a transcriptional repressor of cardiac remodeling, its activity modulated by phosphorylation.
  • Protein kinase C (PKC) and protein kinase D1 (PKD1) are implicated in HDAC5 phosphorylation, but PKD1's role in the heart is not fully understood.

Purpose of the Study:

  • To investigate the function of protein kinase D1 (PKD1) in cardiac myocytes and its role in pathological cardiac remodeling.
  • To elucidate the signaling pathways regulating PKD1 activation and its downstream targets in the heart.
  • To determine the therapeutic potential of targeting PKD1 in heart disease.

Main Methods:

  • Stimulation of cardiac myocytes with hypertrophic agonists and analysis of PKD1 catalytic activity.
  • Investigation of PKC-dependent and -independent mechanisms of PKD1 activation.
  • In vivo studies using rodent models of pathological cardiac remodeling, including small interfering RNA knockdown of PKD1 and overexpression of constitutively active PKD1.

Main Results:

  • PKD1 catalytic activity is stimulated in cardiac myocytes by agonists signaling through G protein-coupled receptors and Rho GTPases.
  • PKD1 activation occurs via both PKC-dependent and -independent pathways.
  • In vivo, cardiac PKD1 is activated during pathological cardiac remodeling, correlating with HDAC5 nuclear export and cardiomyocyte growth. PKD1 knockdown suppressed these effects, while PKD1 overexpression induced dilated cardiomyopathy.

Conclusions:

  • PKD1 plays a critical role in controlling pathological cardiac remodeling.
  • PKD1 phosphorylates and neutralizes HDAC5, thereby regulating cardiomyocyte growth and cardiac remodeling processes.
  • PKD1 represents a potential therapeutic target for managing heart disease.

Related Concept Videos

The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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...
Amplifying Signals via Enzymatic Cascade01:22

Amplifying Signals via Enzymatic Cascade

When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
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,...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...