title: The role of adenylyl cyclase isoform 6 in β-adrenoceptor signalling in murine airways.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Respiratory Pharmacology, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK; MRC-Asthma UK Centre in Allergic Mechanisms of Asthma, London, UK.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Birrell
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Bonvini
authors.forename: Michael A
authors.initials: MA
authors.lastname: Wortley
authors.forename: James
authors.initials: J
authors.lastname: Buckley
authors.forename: Liang
authors.initials: L
authors.lastname: Yew-Booth
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Maher
authors.forename: Nicole
authors.initials: N
authors.lastname: Dale
authors.forename: Eric D
authors.initials: ED
authors.lastname: Dubuis
authors.forename: Maria G
authors.initials: MG
authors.lastname: Belvisi
mesh_terms: D000262:Adenylyl Cyclases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015232:Dinoprostone / Q000031:analogs & derivatives / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D005280:Fenoterol / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000235:genetics; D008297:Male; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D011412:Propanolamines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000819:agonists; D015398:Signal Transduction; D014132:Trachea / Q000187:drug effects / Q000502:physiology*; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*
chemical_list: C499423:9-deoxy-9-chloro-15-deoxy-16-hydroxy-17,17-trimethylene-19,20-didehydroprostaglandin E2; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D007093:Imidazoles; D007527:Isoenzymes; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D058307:Receptors, Prostaglandin E, EP2 Subtype; D005280:Fenoterol; C026777:ICI 118551; C049763:CGP 20712A; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; D015232:Dinoprostone; C037293:denopamine