The role of adenylyl cyclase isoform 6 in β-adrenoceptor signalling in murine airways

M. A. Birrell, S. J. Bonvini, M. A. Wortley, James Buckley, L. Yew-Booth, S. A. Maher, N. Dale, E. D. Dubuis, M. G. Belvisi

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    Abstract

    Background and Purpose Adenylyl cyclase (AC) is a key signalling enzyme for many GPCRs and catalyses the conversion of ATP to cAMP which, in turn, is a crucial determinant of many biological responses. β-Adrenoceptor agonists are prescribed as bronchodilators for asthma and chronic obstructive pulmonary disease, and it is commonly assumed that they elicit their actions via AC-dependent production of cAMP. However, empirical evidence in support of this is lacking and the exact mechanism by which these drugs acts remains elusive. This is partly due to the existence of at least 10 different isoforms of AC and the absence of any truly selective pharmacological inhibitors. Here, we have used genetically modified mice and model systems to establish the role of AC isoforms in the airway responses to β-adrenoceptor agonists. Experimental Approach Receptors mediating responses to β-adrenoceptor agonists in airway smooth muscle (ASM) and sensory nerve were identified in isolated tissue systems. Expression of mRNA for the AC isoforms in ASM and neurones was determined by qPCR. Functional responses were assessed in AC isoform KO mice and wild-type controls. Key Results Airway and vagal tissue expressed mRNA for various isoforms of AC. AC6 was the most prominent isoform. Responses to β-adrenoceptor agonists in tissues from AC6 KO mice were virtually abolished. Conclusions and Implications AC6 played a critical role in relaxation of ASM to β1-adrenoceptor agonists and in modulation of sensory nerves by β1-3-adrenoceptor agonists. These results further unravel the signalling pathway of this extensively prescribed class of medicine.
    Original languageEnglish
    Pages (from-to)131-141
    JournalBritish Journal of Pharmacology
    Volume172
    Issue number1
    Early online date10 Sep 2014
    DOIs
    Publication statusPublished - Jan 2015

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    Adrenergic Receptors
    Protein Isoforms
    RNA Isoforms
    Smooth Muscle
    Bronchodilator Agents
    Chronic Obstructive Pulmonary Disease
    adenylyl cyclase 6
    Asthma
    Adenosine Triphosphate
    Pharmacology
    Neurons
    Enzymes
    Pharmaceutical Preparations

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    Birrell, M. A., Bonvini, S. J., Wortley, M. A., Buckley, J., Yew-Booth, L., Maher, S. A., ... Belvisi, M. G. (2015). The role of adenylyl cyclase isoform 6 in β-adrenoceptor signalling in murine airways. British Journal of Pharmacology, 172(1), 131-141. https://doi.org/10.1111/bph.12905

    The role of adenylyl cyclase isoform 6 in β-adrenoceptor signalling in murine airways. / Birrell, M. A.; Bonvini, S. J.; Wortley, M. A.; Buckley, James; Yew-Booth, L.; Maher, S. A.; Dale, N.; Dubuis, E. D.; Belvisi, M. G.

    In: British Journal of Pharmacology, Vol. 172, No. 1, 01.2015, p. 131-141.

    Research output: Contribution to journalArticle

    Birrell, MA, Bonvini, SJ, Wortley, MA, Buckley, J, Yew-Booth, L, Maher, SA, Dale, N, Dubuis, ED & Belvisi, MG 2015, 'The role of adenylyl cyclase isoform 6 in β-adrenoceptor signalling in murine airways' British Journal of Pharmacology, vol. 172, no. 1, pp. 131-141. https://doi.org/10.1111/bph.12905
    Birrell MA, Bonvini SJ, Wortley MA, Buckley J, Yew-Booth L, Maher SA et al. The role of adenylyl cyclase isoform 6 in β-adrenoceptor signalling in murine airways. British Journal of Pharmacology. 2015 Jan;172(1):131-141. https://doi.org/10.1111/bph.12905
    Birrell, M. A. ; Bonvini, S. J. ; Wortley, M. A. ; Buckley, James ; Yew-Booth, L. ; Maher, S. A. ; Dale, N. ; Dubuis, E. D. ; Belvisi, M. G. / The role of adenylyl cyclase isoform 6 in β-adrenoceptor signalling in murine airways. In: British Journal of Pharmacology. 2015 ; Vol. 172, No. 1. pp. 131-141.
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    AU - Buckley, James

    AU - Yew-Booth, L.

    AU - Maher, S. A.

    AU - Dale, N.

    AU - Dubuis, E. D.

    AU - Belvisi, M. G.

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