Regulation of g protein-coupled receptor-adenylyl cyclase responsiveness in human airway smooth muscle by exogenous and autocrine adenosine

S. J. Mundell, M. E. Olah, Jr Panettieri, J. L. Benovic, R. B. Penn

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Adenosine is a mediator of bronchoconstriction in asthmatics and is believed to mediate its effects through adenosine receptor activation in inflammatory cells, In this study, we identify human airway smooth muscle (ASM) as a direct target of adenosine. Acute exposure of human ASM cultures to adenosine receptor (AR) agonists resulted in rapid accumulation of cyclic adenosine monophosphate (cAMP) with a pharmacologic profile consistent with A2bAR activation. Little or no evidence of A1AR or A3AR expression was suggested on acute addition of various AR ligands, although a Iow level of A1ARs was identified in radioligand binding studies. Treatment with adenosine deaminase suggested that human ASM cultures secrete adenosine that feeds back on A2bARs and regulates basal cAMP levels as well as a small degree of A2bAR, β2AR, and prostaglandin E2 receptor desensitization. When subjected to chronic treatment with AR agonists or agents that enhance accumulation of endogenous, extracellular adenosine, a dual effect of A2bAR desensitization and adenylyl cyclase (AC) sensitization was observed. This AC sensitization was eliminated by pertussis toxin and partially reversed by the A1AR antago 8-cclopentyl-l,3-dipropylxanthine, suggesting a contribnutory role for the A1AR. Overexpression of A1ARs and A2bARs in human ASM cultures resulted in differential effects on basal, agonist-, and AC-mediated cAMP production. These data demonstrate that human ASM is a direct target of exogenous and autocrine adenosine, with effects determined by differential contributions of A2b and A1 adenosine receptors that are time-dependent, Accordingly, the relative distribution and activation of AR subtypes in ASM in vivo may influence airway function in diseases such as asthma and warrant consideration in therapeutic strategies that target ARs or alter nucleotide/nucleoside levels in the airway.

Original languageEnglish (US)
Pages (from-to)155-163
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume24
Issue number2
DOIs
StatePublished - 2001

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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