Role of IP and cADPR in Ca^<2+> -mediated signal transduction in airway cells.

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1. Involvement of cyclic ADP-ribose (cADPR) in ATP-activated K^+ -current in alveolar macrophages. Alveolar macrophages (Mphi) obtained from rat airway-lavage responded to extracellular ATP with a transient outward K^+ current (I_K). I_K was revealed to be activated by Ca^<2+> released intracellularly. Cellular perfusion with IP_3 or cADPR also elicited I_K. The cells perfused with IP_3 still responded to extracellular ATP,whereas those treated with cADPR did not. A cytoplasmic injection of 8-amino-cADPR (a cADPR antagonist) abolished the ATP-induced I_K. The mRNA of CD38, which is ADP-ribosyl cyclase/cADPR hydrolase, was detected in Mphi by RT-PCR.Moreover, Mphi homogenate showed enzymatic activities of cADPR synthesis and hydrolysis. These findings indicate that cADPR operates in alveolar Mphi as a Ca^<2+> -releasing second messenger for extracellular ATP.2. Upregulation of cystic fibrosis transmembrane conductance regulator (CFTR) in SO_2-induced bronchitis in rabbit. To investigate … More abnormalities of epithelial ion transport in inflammatory airways, rabbits exposed to SO_2 for-7 wks were used as a model of bronchitis. In normal trachea, apical ATP induced a transient activation of short circuit current (Isc) followed by a suppression, whereas the bronchitis model exhibited a prolonged activation without suppression. This pathological ATP response was abolished by DPC,a Cl^- channel blocker, or Cl^--free solution. Isoproterenol or adenosine evoked a sustained Isc increase in SO_2-exposed, but not in normal.tracheas. The Northern blot analysis showed a strong expression of CFTR-mRNA in SO2-exposed epithelium. The immunohistochemical study revealed a positive label of CFTR on cells located luminally only in SO_2-exposed rabbits. We concluded that the prolonged ATP-response in the bronchitis model was of a superimposed normal and adenosine-activated current. The latter current was also activated by isoproterenol and appeared as a signature current for the bronchitis airway. Less