Inhibition of CAMP-Dependent PKA Activates β2-Adrenergic Receptor Stimulation of Cytosolic Phospholipase A2 Via Raf-1/MEK/ERK and IP3-Dependent Ca2+ Signaling in Atrial Myocytes

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2016 Dec 16

PMID 27977772

Citations 8

Authors

M R Pabbidi

X Ji

J T Maxwell

G A Mignery

A M Samarel

S L Lipsius

Affiliations

Soon will be listed here.

Abstract

We previously reported in atrial myocytes that inhibition of cAMP-dependent protein kinase (PKA) by laminin (LMN)-integrin signaling activates β2-adrenergic receptor (β2-AR) stimulation of cytosolic phospholipase A2 (cPLA2). The present study sought to determine the signaling mechanisms by which inhibition of PKA activates β2-AR stimulation of cPLA2. We therefore determined the effects of zinterol (0.1 μM; zint-β2-AR) to stimulate ICa,L in atrial myocytes in the absence (+PKA) and presence (-PKA) of the PKA inhibitor (1 μM) KT5720 and compared these results with atrial myocytes attached to laminin (+LMN). Inhibition of Raf-1 (10 μM GW5074), phospholipase C (PLC; 0.5 μM edelfosine), PKC (4 μM chelerythrine) or IP3 receptor (IP3R) signaling (2 μM 2-APB) significantly inhibited zint-β2-AR stimulation of ICa,L in-PKA but not +PKA myocytes. Western blots showed that zint-β2-AR stimulation increased ERK1/2 phosphorylation in-PKA compared to +PKA myocytes. Adenoviral (Adv) expression of dominant negative (dn) -PKCα, dn-Raf-1 or an IP3 affinity trap, each inhibited zint-β2-AR stimulation of ICa,L in + LMN myocytes compared to control +LMN myocytes infected with Adv-βgal. In +LMN myocytes, zint-β2-AR stimulation of ICa,L was enhanced by adenoviral overexpression of wild-type cPLA2 and inhibited by double dn-cPLA2S505A/S515A mutant compared to control +LMN myocytes infected with Adv-βgal. In-PKA myocytes depletion of intracellular Ca2+ stores by 5 μM thapsigargin failed to inhibit zint-β2-AR stimulation of ICa,L via cPLA2. However, disruption of caveolae formation by 10 mM methyl-β-cyclodextrin inhibited zint-β2-AR stimulation of ICa,L in-PKA myocytes significantly more than in +PKA myocytes. We conclude that inhibition of PKA removes inhibition of Raf-1 and thereby allows β2-AR stimulation to act via PKCα/Raf-1/MEK/ERK1/2 and IP3-mediated Ca2+ signaling to stimulate cPLA2 signaling within caveolae. These findings may be relevant to the remodeling of β-AR signaling in failing and/or aging heart, both of which exhibit decreases in adenylate cyclase activity.

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References

Wang L, Wu J, Zhang W, Zhi Y, Wu Y, Jiang R . Effects of aspirin on the ERK and PI3K/Akt signaling pathways in rats with acute pulmonary embolism. Mol Med Rep. 2013; 8(5):1465-71. DOI: 10.3892/mmr.2013.1676. View

Fujimoto T, Nakade S, Miyawaki A, Mikoshiba K, Ogawa K . Localization of inositol 1,4,5-trisphosphate receptor-like protein in plasmalemmal caveolae. J Cell Biol. 1992; 119(6):1507-13. PMC: 2289753. DOI: 10.1083/jcb.119.6.1507. View

Rybin V, Xu X, Lisanti M, Steinberg S . Differential targeting of beta -adrenergic receptor subtypes and adenylyl cyclase to cardiomyocyte caveolae. A mechanism to functionally regulate the cAMP signaling pathway. J Biol Chem. 2000; 275(52):41447-57. DOI: 10.1074/jbc.M006951200. View

Cook S, McCormick F . Inhibition by cAMP of Ras-dependent activation of Raf. Science. 1993; 262(5136):1069-72. DOI: 10.1126/science.7694367. View

Magne S, Couchie D, Pecker F, Pavoine C . Beta(2)-adrenergic receptor agonists increase intracellular free Ca(2+) concentration cycling in ventricular cardiomyocytes through p38 and p42/44 MAPK-mediated cytosolic phospholipase A(2) activation. J Biol Chem. 2001; 276(43):39539-48. DOI: 10.1074/jbc.M100954200. View

Anderson R . The caveolae membrane system. Annu Rev Biochem. 1998; 67:199-225. DOI: 10.1146/annurev.biochem.67.1.199. View

Powis G, Seewald M, Gratas C, Melder D, Riebow J, MODEST E . Selective inhibition of phosphatidylinositol phospholipase C by cytotoxic ether lipid analogues. Cancer Res. 1992; 52(10):2835-40. View

Pavoine C, Magne S, Sauvadet A, Pecker F . Evidence for a beta2-adrenergic/arachidonic acid pathway in ventricular cardiomyocytes. Regulation by the beta1-adrenergic/camp pathway. J Biol Chem. 1999; 274(2):628-37. DOI: 10.1074/jbc.274.2.628. View

Bristow M, Hershberger R, Port J, Minobe W, Rasmussen R . Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol Pharmacol. 1989; 35(3):295-303. View

10.

Ait-Mamar B, Cailleret M, Rucker-Martin C, Bouabdallah A, Candiani G, Adamy C . The cytosolic phospholipase A2 pathway, a safeguard of beta2-adrenergic cardiac effects in rat. J Biol Chem. 2005; 280(19):18881-90. DOI: 10.1074/jbc.M410305200. View

11.

Hirabayashi T, Murayama T, Shimizu T . Regulatory mechanism and physiological role of cytosolic phospholipase A2. Biol Pharm Bull. 2004; 27(8):1168-73. DOI: 10.1248/bpb.27.1168. View

12.

Ping P, Zhang J, Cao X, Li R, Kong D, Tang X . PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits. Am J Physiol. 1999; 276(5):H1468-81. DOI: 10.1152/ajpheart.1999.276.5.H1468. View

13.

Hafner S, Adler H, Mischak H, Janosch P, Heidecker G, Wolfman A . Mechanism of inhibition of Raf-1 by protein kinase A. Mol Cell Biol. 1994; 14(10):6696-703. PMC: 359200. DOI: 10.1128/mcb.14.10.6696-6703.1994. View

14.

Kohno M, Pouyssegur J . Pharmacological inhibitors of the ERK signaling pathway: application as anticancer drugs. Prog Cell Cycle Res. 2003; 5:219-24. View

15.

Wang Y, Dedkova E, Ji X, Blatter L, Lipsius S . Phenylephrine acts via IP3-dependent intracellular NO release to stimulate L-type Ca2+ current in cat atrial myocytes. J Physiol. 2005; 567(Pt 1):143-57. PMC: 1474159. DOI: 10.1113/jphysiol.2005.090035. View

16.

Wang Y, Dedkova E, Steinberg S, Blatter L, Lipsius S . Beta 2-adrenergic receptor signaling acts via NO release to mediate ACh-induced activation of ATP-sensitive K+ current in cat atrial myocytes. J Gen Physiol. 2002; 119(1):69-82. PMC: 2233856. DOI: 10.1085/jgp.119.1.69. View

17.

Yan L, Vatner D, OConnor J, Ivessa A, Ge H, Chen W . Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell. 2007; 130(2):247-58. DOI: 10.1016/j.cell.2007.05.038. View

18.

Brodde O, Zerkowski H, Schranz D, Piotrowski J, Oelert H . Age-dependent changes in the beta-adrenoceptor-G-protein(s)-adenylyl cyclase system in human right atrium. J Cardiovasc Pharmacol. 1995; 26(1):20-6. DOI: 10.1097/00005344-199507000-00004. View

19.

Uddin S, Ahmed M, Hussain A, Assad L, Al-Dayel F, Bavi P . Cyclooxygenase-2 inhibition inhibits PI3K/AKT kinase activity in epithelial ovarian cancer. Int J Cancer. 2009; 126(2):382-94. DOI: 10.1002/ijc.24757. View

20.

Carpenter L, Cordery D, Biden T . Protein kinase Cdelta activation by interleukin-1beta stabilizes inducible nitric-oxide synthase mRNA in pancreatic beta-cells. J Biol Chem. 2000; 276(7):5368-74. DOI: 10.1074/jbc.M010036200. View