skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: ADP‐Induced Ca 2+ Signaling and Proliferation of Rat Ventricular Myofibroblasts Depend on Phospholipase C‐Linked TRP Channels Activation Within Lipid Rafts

Journal Article · · Journal of Cellular Physiology
DOI:https://doi.org/10.1002/jcp.25656· OSTI ID:1401489
 [1];  [1];  [1];  [1];  [2];  [1]
  1. Laboratório de Farmacologia e Neurobiologia, Centro de Investigação Farmacológica e Inovação Medicamentosa (MedInUP), Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto (ICBAS‐UP) Porto Portugal
  2. Laboratório de Farmacologia e Neurobiologia, Centro de Investigação Farmacológica e Inovação Medicamentosa (MedInUP), Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto (ICBAS‐UP) Porto Portugal, Departamento de Química, Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto (ICBAS‐UP) Porto Portugal

Nucleotides released during heart injury affect myocardium electrophysiology and remodeling through P2 purinoceptors activation in cardiac myofibroblasts. ATP and UTP endorse [Ca 2+ ] i accumulation and growth of DDR‐2/α‐SMA‐expressing myofibroblasts from adult rat ventricles via P2Y 4 and P2Y 2 receptors activation, respectively. Ventricular myofibroblasts also express ADP‐sensitive P2Y 1 , P2Y 12 , and P2Y 13 receptors as demonstrated by immunofluorescence confocal microscopy and western blot analysis, but little information exists on ADP effects in these cells. ADP (0.003–3 mM) and its stable analogue, ADPßS (100 μM), caused fast [Ca 2+ ] i transients originated from thapsigargin‐sensitive internal stores, which partially declined to a plateau sustained by capacitative Ca 2+ entry through transient receptor potential (TRP) channels inhibited by 2‐APB (50 μM) and flufenamic acid (100 μM). Hydrophobic interactions between G q/11 ‐coupled P2Y purinoceptors and TRP channels were suggested by prevention of the ADP‐induced [Ca 2+ ] i plateau following PIP 2 depletion with LiCl (10 mM) and cholesterol removal from lipid rafts with methyl‐ß‐cyclodextrin (2 mM). ADP [Ca 2+ ] i transients were insensitive to P2Y 1 , P2Y 12 , and P2Y 13 receptor antagonists, MRS2179 (10μM), AR‐C66096 (0.1 μM), and MRS2211 (10μM), respectively, but were attenuated by suramin and reactive blue‐2 (100 μM) which also blocked P2Y 4 receptors activation by UTP. Cardiac myofibroblasts growth and type I collagen production were favored upon activation of MRS2179‐sensitive P2Y 1 receptors with ADP or ADPßS (30 μM). In conclusion, ADP exerts a dual role on ventricular myofibroblasts: [Ca 2+ ] i transients are mediated by fast‐desensitizing P2Y 4 receptors, whereas the pro‐fibrotic effect of ADP involves the P2Y 1 receptor activation. Data also show that ADP‐induced capacitative Ca 2+ influx depends on phospholipase C‐linked TRP channels opening in lipid raft microdomains. J. Cell. Physiol. 232: 1511–1526, 2017. © 2016 Wiley Periodicals, Inc.

Sponsoring Organization:
USDOE
OSTI ID:
1401489
Journal Information:
Journal of Cellular Physiology, Journal Name: Journal of Cellular Physiology Vol. 232 Journal Issue: 6; ISSN 0021-9541
Publisher:
Wiley Blackwell (John Wiley & Sons)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 10 works
Citation information provided by
Web of Science

References (75)

Cyclodextrin-induced apoptosis in human keratinocytes is caspase-8 dependent and accompanied by mitochondrial cytochrome c release journal November 2006
Pyrimidine Nucleotides with 4-Alkyloxyimino and Terminal Tetraphosphate δ-Ester Modifications as Selective Agonists of the P2Y 4 Receptor journal June 2011
Purinergic signaling in scarring journal January 2016
Regulation of Canonical Transient Receptor Potential (TRPC) Channel Function by Diacylglycerol and Protein Kinase C journal April 2003
Induction of Novel Agonist Selectivity for the ADP-Activated P2Y 1 Receptor Versus the ADP-Activated P2Y 12 and P2Y 13 Receptors by Conformational Constraint of an ADP Analog journal September 2004
Thapsigargin, a tumor promoter, discharges intracellular Ca2+ stores by specific inhibition of the endoplasmic reticulum Ca2(+)-ATPase. journal April 1990
Calcium Signaling via Orai1 Is Essential for Induction of the Nuclear Orphan Receptor Pathway To Drive Th17 Differentiation journal December 2013
Store-operated CRAC channel inhibitors: opportunities and challenges journal May 2016
Pharmacological profiles of cloned mammalian P2Y-receptor subtypes journal June 2006
The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors: The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors journal December 2015
The effects of lithium on the phosphoinositides and inositol phosphates ofNeurospora crassa journal March 1991
Cardioprotective effects of KB-R7943: a novel inhibitor of the reverse mode of Na + /Ca 2+ exchanger journal June 1999
The Na+/Ca2+ exchanger in cardiac ischemia/reperfusion injury journal January 2012
Ion Fluxes through KCa2 (SK) and Cav1 (L-type) Channels Contribute to Chronoselectivity of Adenosine A1 Receptor-Mediated Actions in Spontaneously Beating Rat Atria journal March 2016
Structural and functional characterisation of cardiac fibroblasts journal January 2005
An Introduction to trp Channels journal January 2006
Fibroblasts in myocardial infarction: A role in inflammation and repair journal May 2014
Fibrosis and hypertensive heart disease journal January 2000
STIM1 elevation in the heart results in aberrant Ca2+ handling and cardiomyopathy journal October 2015
Molecular cloning and characterization of rat P2Y 4 nucleotide receptor journal June 1998
Transient Receptor Potential Canonical-3 Channel–Dependent Fibroblast Regulation in Atrial Fibrillation journal October 2012
Inositol phosphates and cell signalling journal September 1989
The Living Scar – Cardiac Fibroblasts and the Injured Heart journal February 2016
Cardiac fibroblasts: At the heart of myocardial remodeling journal August 2009
The Caveolin genes: from cell biology to medicine journal January 2004
Flufenamic acid as an ion channel modulator journal May 2013
A Role for G-Proteins in Directing G-Protein-Coupled Receptor–Caveolae Localization journal November 2012
Myofibroblasts: Trust your heart and let fate decide journal May 2014
A TRPC6-Dependent Pathway for Myofibroblast Transdifferentiation and Wound Healing In Vivo journal October 2012
Pharmacological Modulation of Diacylglycerol-Sensitive TRPC3/6/7 Channels journal January 2011
Potassium channel blockers differentially affect carbachol and (−)-N6-phenylisopropyladenosine on guinea-pig atria journal July 1989
Characterization of ion channels seen in subconfluent human dermal fibroblasts. journal May 1991
A simple method for preparation of cultured cardiac fibroblasts from adult human ventricular tissue journal January 1997
Critical Role for Stromal Interaction Molecule 1 in Cardiac Hypertrophy journal August 2011
THE CARDIAC FIBROBLAST: Therapeutic Target in Myocardial Remodeling and Failure journal September 2005
Purinergic signalling: Purinergic signalling journal January 2006
A distinct de novo expression of Na v 1.5 sodium channels in human atrial fibroblasts differentiated into myofibroblasts : Na journal August 2012
Nucleotide receptors as targets in the pharmacological enhancement of dermal wound healing journal April 2011
K + currents regulate the resting membrane potential, proliferation, and contractile responses in ventricular fibroblasts and myofibroblasts journal June 2005
P2Y 1 Receptor Activation of the TRPV4 Ion Channel Enhances Purinergic Signaling in Satellite Glial Cells journal October 2015
Cardiac Fibroblasts in Cell Culture Systems: Myofibroblasts All Along? journal January 2011
Caveolae Are Highly Immobile Plasma Membrane Microdomains, Which Are not Involved in Constitutive Endocytic Trafficking journal January 2002
Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade journal May 2008
Store-Operated Ca2+ Entry book January 2012
Impact of ectonucleotidases in autonomic nervous functions journal September 2015
The Collagen Receptor DDR2 Is Expressed During Early Cardiac Development
  • Goldsmith, Edie C.; Zhang, Xiadong; Watson, James
  • The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology, Vol. 293, Issue 5 https://doi.org/10.1002/ar.20922
journal May 2009
Characterization of P2Y receptor subtypes functionally expressed on neonatal rat cardiac myofibroblasts journal September 2009
Orai1 and Stim1 regulate normal and hypertrophic growth in cardiomyocytes journal June 2010
Adenosine-5′-triphosphate up-regulates proliferation of human cardiac fibroblasts: ATP and proliferation in human cardiac fibroblasts journal May 2012
Bradykinin-induced Ca2+ signaling in human subcutaneous fibroblasts involves ATP release via hemichannels leading to P2Y12 receptors activation journal January 2013
Stimulation of P2Y receptors activates c-fos gene expression and inhibits DNA synthesis in cultured cardiac fibroblasts journal March 1998
Caveolin-1 alters Ca2+ signal duration through specific interaction with the G q family of G proteins journal April 2008
TRPM7-Mediated Ca 2+ Signals Confer Fibrogenesis in Human Atrial Fibrillation journal March 2010
Uridine triphosphate (UTP) induces profibrotic responses in cardiac fibroblasts by activation of P2Y2 receptors journal September 2010
A TRP to cardiac fibroblast differentiation journal May 2013
Discovery of purinergic signalling, the initial resistance and current explosion of interest: Discovery of purinergic signalling journal August 2012
Caveolae: One Function or Many? journal March 2016
Metabotropic Purinergic Receptors in Lipid Membrane Microdomains journal December 2012
Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart journal August 2006
TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals journal January 2013
2-Aminoethoxydiphenyl borate (2-APB) is a reliable blocker of store-operated Ca 2+ entry but an inconsistent inhibitor of InsP 3 -induced Ca 2+ release journal August 2002
Cellular Mechanisms of Tissue Fibrosis. 6. Purinergic signaling and response in fibroblasts and tissue fibrosis journal May 2014
Cardiac Stim1 Silencing Impairs Adaptive Hypertrophy and Promotes Heart Failure Through Inactivation of mTORC2/Akt Signaling journal April 2016
Human mast cells stimulate fibroblast proliferation, collagen synthesis and lattice contraction: a direct role for mast cells in skin fibrosis journal February 2002
In situ measurement of collagen synthesis by human bone cells with a Sirius Red-based colorimetric microassay: effects of transforming growth factor β2 and ascorbic acid 2-phosphate journal October 1999
Role of ecto-NTPDases on UDP-sensitive P2Y 6 receptor activation during osteogenic differentiation of primary bone marrow stromal cells from postmenopausal women journal February 2012
Cell Patterning: Interaction of Cardiac Myocytes and Fibroblasts in Three-Dimensional Culture journal March 2008
Origins of Cardiac Fibroblasts journal November 2010
Positive Inotropic Effects by Uridine Triphosphate (UTP) and Uridine Diphosphate (UDP) via P2Y 2 and P2Y 6 Receptors on Cardiomyocytes and Release of UTP in Man During Myocardial Infarction journal April 2006
Histamine Induces ATP Release from Human Subcutaneous Fibroblasts, via Pannexin-1 Hemichannels, Leading to Ca 2+ Mobilization and Cell Proliferation journal August 2013
Calcium signaling and the novel anti-proliferative effect of the UTP-sensitive P2Y11 receptor in rat cardiac myofibroblasts journal November 2015
Guidelines for reporting experiments involving animals: the ARRIVE guidelines: Guidelines for reporting experiments involving animals journal July 2010
Caveolae and Caveolins in the Cardiovascular System journal June 2004
Expression of Discoidin Domain Receptor 2 (DDR2) in the Developing Heart journal May 2005
Gα12/13-mediated Up-regulation of TRPC6 Negatively Regulates Endothelin-1-induced Cardiac Myofibroblast Formation and Collagen Synthesis through Nuclear Factor of Activated T Cells Activation journal May 2007

Similar Records

Activation of calcium-sensing receptor increases TRPC3 expression in rat cardiomyocytes
Journal Article · Fri Mar 11 00:00:00 EST 2011 · Biochemical and Biophysical Research Communications · OSTI ID:1401489

Calcium-sensing receptor activation contributed to apoptosis stimulates TRPC6 channel in rat neonatal ventricular myocytes
Journal Article · Fri Apr 16 00:00:00 EDT 2010 · Biochemical and Biophysical Research Communications · OSTI ID:1401489

Regulation of membrane raft recruitment of the bradykinin B2 receptor by close association with the ATP/UTP receptor P2Y2
Journal Article · Mon Oct 15 00:00:00 EDT 2018 · Biochemical and Biophysical Research Communications · OSTI ID:1401489

Related Subjects