CD38/cyclic ADP-ribose-mediated Ca2+ signaling contributes to airway smooth muscle hyper-responsiveness

FASEB J. 2003 Mar;17(3):452-4. doi: 10.1096/fj.02-0450fje. Epub 2003 Jan 2.


We previously demonstrated that cyclic ADP-ribose (cADPR) elicits Ca2+ release in airway smooth muscle (ASM) cells through ryanodine receptor channels. CD38 is a cell surface protein that catalyzes the synthesis and degradation of cADPR. In inflammatory diseases such as asthma, augmented Ca2+ responses and Ca2+ sensitivity contribute to increased ASM contractility in response to agonists. In this study, we investigated the regulation of CD38 expression and the role of cADPR-mediated Ca2+ release in airway inflammation. Human ASM cells in culture between the second and fifth passages were exposed to tumor necrosis factor alpha (TNF-alpha), interleukin 1beta, or interferon gamma, or bovine serum albumin (controls). CD38 expression was measured by reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR, and Western blot analysis, and ADP-ribosyl cyclase activity was assayed with nicotinamide guanine dinucleotide as the substrate. Ca2+ responses to acetylcholine, bradykinin, and thrombin were measured in fura-2AM-loaded cells by fluorescence microscopy. Cytokines caused significant augmentation of CD38 expression, ADP-ribosyl cyclase activity, and Ca2+ responses to the agonists, compared with the control. TNF-alpha effects were greater than those of the other two cytokines. The cADPR antagonist 8-bromo-cADPR attenuated the Ca2+ responses to the agonists in control and cytokine-treated cells, with the magnitude of inhibition correlating with the level of CD38. This study provides the first demonstration of a role for CD38-cADPR signaling in a model of inflammatory airway disease.

MeSH terms

  • ADP-ribosyl Cyclase / antagonists & inhibitors
  • ADP-ribosyl Cyclase / genetics
  • ADP-ribosyl Cyclase / physiology*
  • ADP-ribosyl Cyclase 1
  • Acetylcholine / antagonists & inhibitors
  • Acetylcholine / pharmacology
  • Antigens, CD / genetics
  • Antigens, CD / physiology*
  • Bradykinin / antagonists & inhibitors
  • Bradykinin / pharmacology
  • Bronchial Hyperreactivity / etiology
  • Calcium Signaling*
  • Cells, Cultured
  • Cytokines / pharmacology
  • Humans
  • Membrane Glycoproteins
  • Models, Biological
  • Muscle Contraction
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism*
  • Muscle, Smooth / physiology
  • RNA, Messenger / biosynthesis
  • Respiratory Physiological Phenomena
  • Respiratory System / cytology
  • Respiratory System / metabolism*
  • Thrombin / antagonists & inhibitors
  • Thrombin / pharmacology


  • Antigens, CD
  • Cytokines
  • Membrane Glycoproteins
  • RNA, Messenger
  • ADP-ribosyl Cyclase
  • CD38 protein, human
  • ADP-ribosyl Cyclase 1
  • Thrombin
  • Acetylcholine
  • Bradykinin