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Molecular Pharmacology

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Research ArticleArticle

Facilitatory Interplay in α1a and β2 Adrenoceptor Function Reveals a Non-Gq Signaling Mode: Implications for Diversification of Intracellular Signal Transduction

Alicja J. Copik, Cynthia Ma, Alan Kosaka, Sunil Sahdeo, Andy Trane, Hoangdung Ho, Paul S. Dietrich, Helen Yu, Anthony P. D. W. Ford, Donald Button and Marcos E. Milla
Molecular Pharmacology March 2009, 75 (3) 713-728; DOI: https://doi.org/10.1124/mol.108.050765
Alicja J. Copik
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Cynthia Ma
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Alan Kosaka
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Sunil Sahdeo
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Andy Trane
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Hoangdung Ho
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Paul S. Dietrich
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Helen Yu
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Anthony P. D. W. Ford
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Donald Button
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Marcos E. Milla
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Abstract

Agonist occupied α1-adrenoceptors (α1-ARs) engage several signaling pathways, including phosphatidylinositol hydrolysis, calcium mobilization, arachidonic acid release, mitogen-activated protein (MAP) kinase activation, and cAMP accumulation. The natural agonist norepinephrine (NE) activates with variable affinity and intrinsic efficacy all adrenoceptors, and in cells that coexpress α1- and β-AR subtypes, such as cardiomyocytes, this leads to coactivation of multiple downstream pathways. This may result in pathway cross-talk with significant consequences to heart physiology and pathologic state. To dissect signaling components involved specifically in α1A- and β2-AR signal interplay, we have developed a recombinant model system that mimics the levels of receptor expression observed in native cells. We followed intracellular Ca2+ mobilization to monitor in real time the activation of both Gq and Gs pathways. We found that coactivation of α1A- and β2-AR by the nonselective agonist NE or via a combination of the highly selective α1A-AR agonist A61603 and the β-selective agonist isoproterenol led to increases in Ca2+ influx from the extracellular compartment relative to stimulation with A61603 alone, with no effect on the associated transient release of Ca2+ from intracellular stores. This effect became more evident upon examination of an α1A-AR variant exhibiting a partial defect in coupling to Gq, and we attribute it to potentiation of a non Gq-pathway, uncovered by application of a combination of xestospongin C, an endoplasmic reticulum inositol 1,4,5-triphosphate receptor blocker, and 2-aminoethoxydiphenyl borate, a nonselective storeoperated Ca2+ entry channel blocker. We also found that stimulation with A61603 of a second α1A-AR variant entirely unable to signal induced no Ca2+ unless β2-AR was concomitantly activated. These results may be accounted for by the presence of α1A/β2-AR heterodimers or alternatively by specific adrenoceptor signal cross-talk resulting in distinct pharmacological behavior. Finally, our findings provide a new conceptual framework to rationalize outcomes from clinical studies targeting α- and β-adrenoceptors.

Footnotes

  • ABBREVIATIONS: GPCR, G protein-coupled receptor; 2-APB, 2-aminoethoxydiphenyl borate; A61603, N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]methanesulfonamide hydrobromide; AR, adrenoceptor; CYP, cyanopindolol; EBNA, Epstein-Barr virus nuclear antigen; ERK, extracellular signal-regulated kinase; FRET, Förster resonance energy transfer; H89, N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline; HEK, human embryonic kidney; ICI 118551, erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol; ICL-3, third intracellular loop; IP, inositol phosphate; IP3, inositol 1,4,5-triphosphate; IP3R, inositol 1,4,5-triphosphate receptor; MDL12,330A, cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine hydrochloride; NaBu, sodium butyrate; NE, norepinephrine; NECA, 5′-N-ethylcarboxamidoadenosine; PKA, cAMP-dependent protein kinase; RS100329, 5-methyl-3-[3-[4-[2-(2,2,2,-trifluoroethoxy)phenyl]-1-piperazinyl]propyl]-2,4-(1H)-pyrimidinedione; SOC, store-operated Ca2+; TCM, tetracysteine motif (CCPGCC).

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received July 24, 2008.
    • Accepted December 24, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (3)
Molecular Pharmacology
Vol. 75, Issue 3
1 Mar 2009
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Research ArticleArticle

Facilitatory Interplay in α1a and β2 Adrenoceptor Function Reveals a Non-Gq Signaling Mode: Implications for Diversification of Intracellular Signal Transduction

Alicja J. Copik, Cynthia Ma, Alan Kosaka, Sunil Sahdeo, Andy Trane, Hoangdung Ho, Paul S. Dietrich, Helen Yu, Anthony P. D. W. Ford, Donald Button and Marcos E. Milla
Molecular Pharmacology March 1, 2009, 75 (3) 713-728; DOI: https://doi.org/10.1124/mol.108.050765

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Research ArticleArticle

Facilitatory Interplay in α1a and β2 Adrenoceptor Function Reveals a Non-Gq Signaling Mode: Implications for Diversification of Intracellular Signal Transduction

Alicja J. Copik, Cynthia Ma, Alan Kosaka, Sunil Sahdeo, Andy Trane, Hoangdung Ho, Paul S. Dietrich, Helen Yu, Anthony P. D. W. Ford, Donald Button and Marcos E. Milla
Molecular Pharmacology March 1, 2009, 75 (3) 713-728; DOI: https://doi.org/10.1124/mol.108.050765
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