The role of adenylyl cyclase isoform 6 in β‐adrenoceptor signalling in murine airways. (24th November 2014)

• Record Type: Journal Article
• Authors: Birrell, Mark A; Bonvini, Sara J; Wortley, Michael A; Buckley, James; Yew‐Booth, Liang; Maher, Sarah A; Dale, Nicole; Dubuis, Eric D; Belvisi, Maria G
• Is Part Of: British journal of pharmacology. Volume 172:Number 1(2015:Jan.)
• Page Start: 131
• Page End: 141
• Publication Date: 2014-11-24
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12905
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12905-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>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.</p> </sec> <sec id="bph12905-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>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.</p> </sec> <sec id="bph12905-sec-0003" sec-type="section"> <title>Key Results</title> <p>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.</p> </sec> <sec id="bph12905-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>AC6 played a critical role in relaxation of ASM to β<sub>1</sub>‐adrenoceptor agonists and in modulation of sensory nerves by β<sub>1‐3</sub>‐adrenoceptor agonists. These results further unravel the signalling pathway of this extensively prescribed class of medicine.</p> </sec> </abstract>