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Membrane Microdomains and cAMP Compartmentation in Cardiac Myocytes

  • Shailesh R. Agarwal
  • Rennolds S. Ostrom
  • Robert D. Harvey
Chapter
Part of the Cardiac and Vascular Biology book series (Abbreviated title: Card. vasc. biol.)

Abstract

Signaling through the diffusible second messenger, 3′,5′-cyclic adenosine monophosphate (cAMP) is critical to the regulation of cardiac function. Several different G-protein-coupled receptors, including β-adrenergic receptors, muscarinic receptors, and E-type prostaglandin receptors, elicit distinct responses using this ubiquitous second messenger. One critical paradigm that has emerged to explain this behavior is that cAMP signaling is compartmentalized. Spatially confining specific receptors and their downstream effector proteins to form subcellular signaling complexes has been proposed to allow for the high efficiency and fidelity in producing specific functional responses. In cardiac myocytes, lipid rafts created by cholesterol- and sphingolipid-rich membrane microdomains have been demonstrated to act as one means of sorting appropriate receptors and corresponding effectors to relevant subcellular locations. Caveolae, which represent a specific subset of lipid rafts, can dynamically attract or exclude specific signaling proteins through a variety of mechanisms to create highly localized and self-sufficient multi-molecular signaling complexes. Furthermore, disruption of this organization in disease states such as heart failure has been found to alter cAMP responses. In this review, we summarize the current understanding of the role of membrane domains in cAMP signaling in cardiac myocytes. We also highlight the insights gained from previous studies to offer new avenues of research in this expanding field of study.

Keywords

Caveolae Lipid rafts Cardiac myocytes G-protein-coupled receptors Compartmentation Cyclic adenosine monophosphate 

Abbreviations

AC

Adenylyl cyclase

ACh

Acetylcholine

AKAP

A-kinase-anchoring protein

cAMP

3′,5′-Cyclic adenosine monophosphate

Cav3

Caveolin 3

CSD

Caveolin scaffolding domain

DRM

Detergent-resistant membrane

EC

Excitation-contraction

eNOS

Endothelial nitric oxide synthase

Epac

Exchange protein directly activated by cAMP

EPR

E-type prostaglandin receptor

GPCR

G-protein-coupled receptor

GPI

Glycosylphosphatidylinositol

M2R

M2 muscarinic receptor

MβCD

Methyl-β-cyclodextrin

NO

Nitric oxide

PDE

Phosphodiesterase

PKA

Protein kinase A

PLB

Phospholamban

SICM

Scanning ion conductance microscopy

SR

Sarcoplasmic reticulum

T tubule

Transverse tubule

β1AR

β1-Adrenergic receptor

β2AR

β2-Adrenergic receptor

Notes

Acknowledgements

This work was supported by the National Institutes of Health grants GM101928 and GM107094.

Compliance with Ethical Standards

Conflict of Interest Statement

The authors declare that they have no conflict of interest.

References

  1. Agarwal SR, Clancy CE, Harvey RD (2016) Mechanisms restricting diffusion of intracellular cAMP. Sci Rep 6:19577. doi: 10.1038/srep19577 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Agarwal SR, Macdougall DA, Tyser R et al (2011) Effects of cholesterol depletion on compartmentalized cAMP responses in adult cardiac myocytes. J Mol Cell Cardiol 50:500–509Google Scholar
  3. Agarwal SR, Yang PC, Rice M et al (2014) Role of membrane microdomains in compartmentation of cAMP signaling. PLoS One 9:e95835CrossRefPubMedPubMedCentralGoogle Scholar
  4. Allen JA, Halverson-Tamboli RA, Rasenick MM (2007) Lipid raft microdomains and neurotransmitter signalling. Nat Rev Neurosci 8:128–140CrossRefPubMedGoogle Scholar
  5. Aprigliano O, Rybin VO, Pak E et al (1997) β1- and β2-adrenergic receptors exhibit differing susceptibility to muscarinic accentuated antagonism. Am J Physiol 272:H2726–H2735PubMedGoogle Scholar
  6. Baillie GS, Sood A, McPhee I et al (2003) beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proc Natl Acad Sci U S A 100:940–945CrossRefPubMedPubMedCentralGoogle Scholar
  7. Balijepalli RC, Foell JD, Hall DD et al (2006) Localization of cardiac L-type Ca(2+) channels to a caveolar macromolecular signaling complex is required for beta(2)-adrenergic regulation. Proc Natl Acad Sci U S A 103:7500–7505CrossRefPubMedPubMedCentralGoogle Scholar
  8. Balligand JL (1999) Regulation of cardiac beta-adrenergic response by nitric oxide. Cardiovasc Res 43:607–620CrossRefPubMedGoogle Scholar
  9. Belevych AE, Harvey RD (2000) Muscarinic inhibitory and stimulatory regulation of the L-type Ca2+ current is not altered in cardiac ventricular myocytes from mice lacking endothelial nitric oxide synthase. J Physiol (Lond) 528:279–289CrossRefGoogle Scholar
  10. Belevych AE, Sims C, Harvey RD (2001) ACh-induced rebound stimulation of L-type Ca(2+) current in guinea-pig ventricular myocytes, mediated by Gbetagamma-dependent activation of adenylyl cyclase. J Physiol (Lond) 536:677–692CrossRefGoogle Scholar
  11. Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415:198–205CrossRefPubMedGoogle Scholar
  12. Bethani I, Skanland SS, Dikic I et al (2010) Spatial organization of transmembrane receptor signalling. EMBO J 29:2677–2688CrossRefPubMedPubMedCentralGoogle Scholar
  13. Brown DA (2006) Lipid rafts, detergent-resistant membranes, and raft targeting signals. Physiology 21:430–439CrossRefPubMedGoogle Scholar
  14. Brown DA, Rose JK (1992) Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell 68:533–544CrossRefPubMedGoogle Scholar
  15. Brunton LL, Hayes JS, Mayer SE (1979) Hormonally specific phosphorylation of cardiac troponin I and activation of glycogen phosphorylase. Nature 280:78–80CrossRefPubMedGoogle Scholar
  16. Buxton IL, Brunton LL (1983) Compartments of cyclic AMP and protein kinase in mammalian cardiomyocytes. J Biol Chem 258:10233–10239PubMedGoogle Scholar
  17. Calaghan S, White E (2006) Caveolae modulate excitation-contraction coupling and beta2-adrenergic signalling in adult rat ventricular myocytes. Cardiovasc Res 69:816–824CrossRefPubMedGoogle Scholar
  18. Chen-Izu Y, Xiao RP, Izu LT et al (2000) G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels. Biophys J 79:2547–2556CrossRefPubMedPubMedCentralGoogle Scholar
  19. Chini B, Parenti M (2004) G-protein coupled receptors in lipid rafts and caveolae: how, when and why do they go there? J Mol Endocrinol 32:325–338CrossRefPubMedGoogle Scholar
  20. Corbin JD, Sugden PH, Lincoln TM et al (1977) Compartmentalization of adenosine 3′:5′-monophosphate and adenosine 3′:5′-monophosphate-dependent protein kinase in heart tissue. J Biol Chem 252:3854–3861PubMedGoogle Scholar
  21. Defer N, Best-Belpomme M, Hanoune J (2000) Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. Am J Physiol 279:F400–F416Google Scholar
  22. Devic E, Xiang Y, Gould D et al (2001) Beta-adrenergic receptor subtype-specific signaling in cardiac myocytes from beta(1) and beta(2) adrenoceptor knockout mice. Mol Pharmacol 60:577–583PubMedGoogle Scholar
  23. Dhein S, Van Koppen CJ, Brodde OE (2001) Muscarinic receptors in the mammalian heart. Pharmacol Res 44:161–182CrossRefPubMedGoogle Scholar
  24. Di Benedetto G, Zoccarato A, Lissandron V et al (2008) Protein kinase A type I and type II define distinct intracellular signaling compartments. Circ Res 103:836–844CrossRefPubMedGoogle Scholar
  25. Eggeling C, Ringemann C, Medda R et al (2009) Direct observation of the nanoscale dynamics of membrane lipids in a living cell. Nature 457:1159–1162CrossRefPubMedGoogle Scholar
  26. Feron O, Dessy C, Opel DJ et al (1998) Modulation of the endothelial nitric-oxide synthase-caveolin interaction in cardiac myocytes. Implications for the autonomic regulation of heart rate. J Biol Chem 273:30249–30254CrossRefPubMedGoogle Scholar
  27. Feron O, Smith TW, Michel T et al (1997) Dynamic targeting of the agonist-stimulated m2 muscarinic acetylcholine receptor to caveolae in cardiac myocytes. J Biol Chem 272:17744–17748CrossRefPubMedGoogle Scholar
  28. Fischmeister R, Castro LR, Abi-Gerges A et al (2006) Compartmentation of cyclic nucleotide signaling in the heart: the role of cyclic nucleotide phosphodiesterases. Circ Res 99:816–828CrossRefPubMedGoogle Scholar
  29. Gancedo JM (2013) Biological roles of cAMP: variations on a theme in the different kingdoms of life. Biol Rev Camb Philos Soc 88:645–668CrossRefPubMedGoogle Scholar
  30. Gödecke A, Heinicke T, Kamkin A et al (2001) Inotropic response to beta-adrenergic receptor stimulation and anti- adrenergic effect of ACh in endothelial NO synthase-deficient mouse hearts. J Physiol (Lond) 532:195–204CrossRefPubMedCentralGoogle Scholar
  31. Hanson MA, Cherezov V, Griffith MT et al (2008) A specific cholesterol binding site is established by the 2.8 A structure of the human beta2-adrenergic receptor. Structure 16:897–905CrossRefPubMedPubMedCentralGoogle Scholar
  32. Hartzell HC (1988) Regulation of cardiac ion channels by catecholamines, acetylcholine and second messenger systems. Prog Biophys Mol Biol 52:165–247CrossRefPubMedGoogle Scholar
  33. Harvey RD, Belevych AE (2003) Muscarinic regulation of cardiac ion channels. Br J Pharmacol 139:1074–1084CrossRefPubMedPubMedCentralGoogle Scholar
  34. Harvey RD, Calaghan SC (2012) Caveolae create local signalling domains through their distinct protein content, lipid profile and morphology. J Mol Cell Cardiol 52:366–375CrossRefPubMedGoogle Scholar
  35. Hayes JS, Brunton LL, Brown JH et al (1979) Hormonally specific expression of cardiac protein kinase activity. Proc Natl Acad Sci U S A 76:1570–1574CrossRefPubMedPubMedCentralGoogle Scholar
  36. Hayes JS, Brunton LL, Mayer SE (1980) Selective activation of particulate cAMP-dependent protein kinase by isoproterenol and prostaglandin E1. J Biol Chem 255:5113–5119PubMedGoogle Scholar
  37. Head BP, Patel HH, Roth DM et al (2005) G-protein-coupled receptor signaling components localize in both sarcolemmal and intracellular caveolin-3-associated microdomains in adult cardiac myocytes. J Biol Chem 280:31036–31044CrossRefPubMedGoogle Scholar
  38. Head BP, Patel HH, Roth DM et al (2006) Microtubules and actin microfilaments regulate lipid raft/caveolae localization of adenylyl cyclase signaling components. J Biol Chem 281:26391–26399CrossRefPubMedGoogle Scholar
  39. Iancu RV, Jones SW, Harvey RD (2007) Compartmentation of cAMP signaling in cardiac myocytes: a computational study. Biophys J 92:3317–3331CrossRefPubMedPubMedCentralGoogle Scholar
  40. Iancu RV, Ramamurthy G, Warrier S et al (2008) Cytoplasmic cAMP concentrations in intact cardiac myocytes. Am J Physiol Cell Physiol 295:C414–C422CrossRefPubMedPubMedCentralGoogle Scholar
  41. Insel PA, Head BP, Patel HH et al (2005) Compartmentation of G-protein-coupled receptors and their signalling components in lipid rafts and caveolae. Biochem Soc Trans 33:1131–1134CrossRefPubMedGoogle Scholar
  42. Ishikawa Y, Homcy CJ (1997) The adenylyl cyclases as integrators of transmembrane signal transduction. Circ Res 80:297–304CrossRefPubMedGoogle Scholar
  43. Jacobson K, Mouritsen OG, Anderson RGW (2007) Lipid rafts: at a crossroad between cell biology and physics. Nat Cell Biol 9:7–14CrossRefPubMedGoogle Scholar
  44. Keely SL (1977) Activation of cAMP-dependent protein kinase without a corresponding increase in phosphorylase activity. Res Commun Chem Pathol Pharmacol 18:283–290PubMedGoogle Scholar
  45. Kuschel M, Zhou YY, Cheng H et al (1999a) G(i) protein-mediated functional compartmentalization of cardiac beta(2)-adrenergic signaling. J Biol Chem 274:22048–22052CrossRefPubMedGoogle Scholar
  46. Kuschel M, Zhou YY, Spurgeon HA et al (1999b) Beta2-adrenergic cAMP signaling is uncoupled from phosphorylation of cytoplasmic proteins in canine heart. Circulation 99:2458–2465CrossRefPubMedGoogle Scholar
  47. Kuznetsov V, Pak E, Robinson RB et al (1995) β2-adrenergic receptor actions in neonatal and adult rat ventricular myocytes. Circ Res 76:40–52CrossRefPubMedGoogle Scholar
  48. Levin KR, Page E (1980) Quantitative studies on plasmalemmal folds and caveolae of rabbit ventricular myocardial cells. Circ Res 46:244–255CrossRefPubMedGoogle Scholar
  49. Levy MN (1971) Sympathetic-parasympathetic interactions in the heart. Circ Res:437–445Google Scholar
  50. Löffelholz K, Pappano AJ (1985) The parasympathetic neuroeffector junction of the heart. Pharmacol Rev 37:1–24PubMedGoogle Scholar
  51. Macdougall DA, Agarwal SR, Stopford EA et al (2012) Caveolae compartmentalise beta2-adrenoceptor signals by curtailing cAMP production and maintaining phosphatase activity in the sarcoplasmic reticulum of the adult ventricular myocyte. J Mol Cell Cardiol 52:388–400Google Scholar
  52. Melkonian KA, Ostermeyer AG, Chen JZ et al (1999) Role of lipid modifications in targeting proteins to detergent-resistant membrane rafts. Many raft proteins are acylated, while few are prenylated. J Biol Chem 274:3910–3917CrossRefPubMedGoogle Scholar
  53. Mika D, Leroy J, Vandecasteele G et al (2012) PDEs create local domains of cAMP signaling. J Mol Cell Cardiol 52:323–329CrossRefPubMedGoogle Scholar
  54. Moffett S, Brown DA, Linder ME (2000) Lipid-dependent targeting of G proteins into rafts. J Biol Chem 275:2191–2198CrossRefPubMedGoogle Scholar
  55. Nichols CB, Rossow CF, Navedo MF et al (2010) Sympathetic stimulation of adult cardiomyocytes requires association of AKAP5 with a subpopulation of L-type calcium channels. Circ Res 107:747–756CrossRefPubMedGoogle Scholar
  56. Nikolaev VO, Bunemann M, Hein L et al (2004) Novel single chain cAMP sensors for receptor-induced signal propagation. J Biol Chem 279:37215–37218CrossRefPubMedGoogle Scholar
  57. Nikolaev VO, Bunemann M, Schmitteckert E et al (2006) Cyclic AMP imaging in adult cardiac myocytes reveals far-reaching beta-1 adrenergic but locally confined beta-2 adrenergic receptor-mediated signaling. Circ Res 99:1084–1091CrossRefPubMedGoogle Scholar
  58. Nikolaev VO, Moshkov A, Lyon AR et al (2010) Beta2-adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science 327:1653–1657CrossRefPubMedGoogle Scholar
  59. Ostrom RS, Bundey RA, Insel PA (2004) Nitric oxide inhibition of adenylyl cyclase type 6 activity is dependent upon lipid rafts and caveolin signaling complexes. J Biol Chem 279:19846–19853CrossRefPubMedGoogle Scholar
  60. Ostrom RS, Gregorian C, Drenan RM et al (2001) Receptor number and caveolar co-localization determine receptor coupling efficiency to adenylyl cyclase. J Biol Chem 276:42063–42069CrossRefPubMedGoogle Scholar
  61. Ostrom RS, Insel PA (2004) The evolving role of lipid rafts and caveolae in G protein-coupled receptor signaling: implications for molecular pharmacology. Br J Pharmacol 143:235–245CrossRefPubMedPubMedCentralGoogle Scholar
  62. Ostrom RS, Post SR, Pa I (2000a) Stoichiometry and compartmentation in G protein-coupled receptor signaling: implications for therapeutic interventions involving G(s). J Pharmacol Exp Ther 294:407–412PubMedGoogle Scholar
  63. Ostrom RS, Violin JD, Coleman S et al (2000b) Selective enhancement of beta-adrenergic receptor signaling by overexpression of adenylyl cyclase type 6: colocalization of receptor and adenylyl cyclase in caveolae of cardiac myocytes. Mol Pharmacol 57:1075–1079PubMedGoogle Scholar
  64. Pagano M, Clynes MA, Masada N et al (2009) Insights into the residence in lipid rafts of adenylyl cyclase AC8 and its regulation by capacitative calcium entry. Am J Physiol Cell Physiol 296:C607–C619CrossRefPubMedPubMedCentralGoogle Scholar
  65. Perino A, Ghigo A, Scott JD et al (2012) Anchoring proteins as regulators of signaling pathways. Circ Res 111:482–492CrossRefPubMedPubMedCentralGoogle Scholar
  66. Perry SJ, Baillie GS, Kohout TA et al (2002) Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science 298:834–836CrossRefPubMedGoogle Scholar
  67. Pugh SD, MacDougall DA, Agarwal SR et al (2014) Caveolin contributes to the modulation of basal and beta-adrenoceptor stimulated function of the adult rat ventricular myocyte by simvastatin: a novel pleiotropic effect. PLoS One 9:e106905CrossRefPubMedPubMedCentralGoogle Scholar
  68. Resh MD (2006) Trafficking and signaling by fatty-acylated and prenylated proteins. Nat Chem Biol 2:584–590CrossRefPubMedGoogle Scholar
  69. Richards M, Lomas O, Jalink K et al (2016) Intracellular tortuosity underlies slow cAMP diffusion in adult ventricular myocytes. Cardiovasc Res 110:395–407CrossRefPubMedPubMedCentralGoogle Scholar
  70. Robison GA, Butcher RW, Sutherland EW (1968) Cyclic AMP. Annu Rev Biochem 37:149–174CrossRefPubMedGoogle Scholar
  71. Rybin VO, Xu X, Lisanti MP et al (2000) 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 275:41447–41457CrossRefPubMedGoogle Scholar
  72. Scott JD, Dessauer CW, Tasken K (2013) Creating Order from Chaos: Cellular Regulation by Kinase Anchoring. Annu Rev Pharmacol Toxicol 53:187–210CrossRefPubMedGoogle Scholar
  73. Scriven DR, Dan P, Moore ED (2000) Distribution of proteins implicated in excitation-contraction coupling in rat ventricular myocytes. Biophys J 79:2682–2691CrossRefPubMedPubMedCentralGoogle Scholar
  74. Shenoy SK, Lefkowitz RJ (2011) beta-Arrestin-mediated receptor trafficking and signal transduction. Trends Pharmacol Sci 32:521–533CrossRefPubMedPubMedCentralGoogle Scholar
  75. Singer SJ, Nicolson GL (1972) The fluid mosaic model of the structure of cell membranes. Science 175:720–731CrossRefPubMedGoogle Scholar
  76. Sprenger JU, Nikolaev VO (2013) Biophysical techniques for detection of cAMP and cGMP in living cells. Int J Mol Sci 14:8025–8046CrossRefPubMedPubMedCentralGoogle Scholar
  77. Steinberg SF (1999) The molecular basis for distinct beta-adrenergic receptor subtype actions in cardiomyocytes. Circ Res 85:1101–1111CrossRefPubMedGoogle Scholar
  78. Steinberg SF, Brunton LL (2001) Compartmentation of G protein-coupled signaling pathways in cardiac myocytes. Annu Rev Pharmacol Toxicol 41:751–773CrossRefPubMedGoogle Scholar
  79. Sunahara RK, Dessauer CW, Gilman AG (1996) Complexity and diversity of mammalian adenylyl cyclases. Annu Rev Pharmacol Toxicol 36:461–480CrossRefPubMedGoogle Scholar
  80. Timofeyev V, Myers RE, Kim HJ et al (2013) Adenylyl cyclase subtype-specific compartmentalization: differential regulation of L-type Ca2+ current in ventricular myocytes. Circ Res 112:1567–1576CrossRefPubMedPubMedCentralGoogle Scholar
  81. Tolkovsky AM, Levitzki A (1978) Mode of coupling between the beta-adrenergic receptor and adenylate cyclase in turkey erythrocytes. Biochemistry 17:3795CrossRefPubMedGoogle Scholar
  82. Toya Y, Schwencke C, Couet J et al (1998) Inhibition of adenylyl cyclase by caveolin peptides. Endocrinology 139:2025–2031CrossRefPubMedGoogle Scholar
  83. Vandecasteele G, Eschenhagen T, Scholz H et al (1999) Muscarinic and beta-adrenergic regulation of heart rate, force of contraction and calcium current is preserved in mice lacking endothelial nitric oxide synthase. Nat Med 5:331–334CrossRefPubMedGoogle Scholar
  84. Wang YG, Rechenmacher CE, Lipsius SL (1998) Nitric oxide signaling mediates stimulation of L-type Ca2+ current elicited by withdrawal of acetylcholine in cat atrial myocytes. J Gen Physiol 111:113–125CrossRefPubMedPubMedCentralGoogle Scholar
  85. Warrier S, Belevych AE, Ruse M et al (2005) Beta-adrenergic and muscarinic receptor induced changes in cAMP activity in adult cardiac myocytes detected using a FRET based biosensor. Am J Physiol Cell Physiol 289:C455–C461CrossRefPubMedGoogle Scholar
  86. Warrier S, Ramamurthy G, Eckert RL et al (2007) cAMP microdomains and L-type Ca2+ channel regulation in guinea-pig ventricular myocytes. J Physiol (Lond) 580:765–776CrossRefGoogle Scholar
  87. Wickman K, Clapham DE (1995) Ion channel regulation by G proteins. Physiol Rev 75:865–885CrossRefPubMedGoogle Scholar
  88. Williams TM, Lisanti MP (2004) The caveolin proteins. Genome Biol 5:214CrossRefPubMedPubMedCentralGoogle Scholar
  89. Willoughby D, Cooper DM (2007) Organization and Ca2+ regulation of adenylyl cyclases in cAMP microdomains. Physiol Rev 87:965–1010CrossRefPubMedGoogle Scholar
  90. Wright PT, Nikolaev VO, O’Hara T et al (2014) Caveolin-3 regulates compartmentation of cardiomyocyte beta2-adrenergic receptor-mediated cAMP signaling. J Mol Cell Cardiol 67:38–48CrossRefPubMedGoogle Scholar
  91. Xiang Y, Devic E, Kobilka B (2002a) The PDZ binding motif of the beta 1 adrenergic receptor modulates receptor trafficking and signaling in cardiac myocytes. J Biol Chem 277:33783–33790CrossRefPubMedGoogle Scholar
  92. Xiang Y, Kobilka B (2003) The PDZ-binding motif of the beta2-adrenoceptor is essential for physiologic signaling and trafficking in cardiac myocytes. Proc Natl Acad Sci U S A 100:10776–10781CrossRefPubMedPubMedCentralGoogle Scholar
  93. Xiang Y, Naro F, Zoudilova M et al (2005) Phosphodiesterase 4D is required for beta2 adrenoceptor subtype-specific signaling in cardiac myocytes. Proc Natl Acad Sci U S A 102:909–914CrossRefPubMedPubMedCentralGoogle Scholar
  94. Xiang Y, Rybin VO, Steinberg SF et al (2002b) Caveolar localization dictates physiologic signaling of beta 2-adrenoceptors in neonatal cardiac myocytes. J Biol Chem 277:34280–34286CrossRefPubMedGoogle Scholar
  95. Xiao RP (2001) Beta-adrenergic signaling in the heart: dual coupling of the beta2-adrenergic receptor to G(s) and G(i) proteins. Science STKE 2001:RE15PubMedGoogle Scholar
  96. Xiao RP, Avdonin P, Zhou YY et al (1999) Coupling of beta2-adrenoceptor to Gi proteins and its physiological relevance in murine cardiac myocytes. Circ Res 84:43–52CrossRefPubMedGoogle Scholar
  97. Xiao RP, Hohl C, Altschuld R et al (1994) Beta 2-adrenergic receptor-stimulated increase in cAMP in rat heart cells is not coupled to changes in Ca2+ dynamics, contractility, or phospholamban phosphorylation. J Biol Chem 269:19151–19156PubMedGoogle Scholar
  98. Xiao RP, Ji X, Lakatta EG (1995) Functional coupling of the beta 2-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. Mol Pharmacol 47:322–329PubMedGoogle Scholar
  99. Yang PC, Boras BW, Jeng MT et al (2016) A computational modeling and simulation approach to investigate mechanisms of subcellular cAMP compartmentation. PLoS Comput Biol 12:e1005005CrossRefPubMedPubMedCentralGoogle Scholar
  100. Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295:1711–1715CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Shailesh R. Agarwal
    • 1
  • Rennolds S. Ostrom
    • 2
  • Robert D. Harvey
    • 1
  1. 1.Department of PharmacologyUniversity of Nevada School of MedicineRenoUSA
  2. 2.Department of Biomedical and Pharmaceutical SciencesChapman University School of PharmacyIrvineUSA

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