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Recently, we discovered a cholinergic mechanism that inhibits the ATP-dependent release of interleukin-1ß (IL-1ß) by human monocytes via nicotinic acetylcholine receptors (nAChRs) composed of a7, a9 and/or a10 subunits. Furthermore, we identified phosphocholine and dipalmitoylphosphatidylcholine as novel nicotinic agonists that elicit metabotropic activity at monocytic nAChR. Interestingly, phosphocholine does not provoke ion channel responses at conventional nAChRs composed of subunits a9 and a10. The purpose of this study is to determine the composition of nAChRs necessary for nicotinic signaling in monocytic cells and to test the hypothesis that common metabolites of phosphatidylcholines, lysophosphatidylcholine and glycerophosphocholine, function as nAChR agonists. In peripheral blood mononuclear cells from nAChR gene-deficient mice we demonstrated that inhibition of adenosine triphosphate (ATP)-dependent release of IL-1ß by acetylcholine, nicotine and phosphocholine depends on subunits a7, a9 and a10. Using a panel of nAChR antagonists and siRNA technology we confirmed the involvement of these subunits in the control of IL-1ß release in the human monocytic cell line U937. Furthermore, we showed that lysophosphatidylcholine (C16:0) and glycerophosphocholine efficiently inhibit ATP-dependent release of IL-1ß. Of note, the inhibitory effects mediated by lysophosphatidylcholine and glycerophosphocholine depend on nAChR subunits a9 and a10, but only to a small degree on a7. In Xenopus laevis oocytes heterologously expressing different combinations of human a7, a9 or a10 subunits, acetylcholine induced canonical ion channel activity, whereas lysophosphatidylcholine, glycerophosphocholine and phosphocholine did not. In conclusion, we demonstrate that canonical nicotinic agonists and phosphocholine elicit metabotropic nAChR activity in monocytes via interaction of nAChR subunits a7, a9 and a10. For the metabotropic signaling of lysophosphatidylcholine and glycerophosphocholine, nAChR subunits a9 and a10 are needed, whereas a7 is virtually dispensable. Furthermore, molecules bearing a phosphocholine group in general seem to regulate immune functions without perturbing canonical ion channel functions of nAChR.

Hydrogen sulfide (H2S) has been recognized as a signalling molecule which affects the activity of ion channels and transporters in epithelial cells. The cystic fibrosis transmembrane conductance regulator (CFTR) is an epithelial anion channel and a key regulator of electrolyte and fluid homeostasis. In this study, we investigated the regulation of CFTR by H2S. Human CFTR was heterologously expressed in Xenopus oocytes and its activity was electrophysiologically measured by microelectrode recordings. The H2S-forming sulphur salt Na2S as well as the slow-releasing H2S-liberating compound GYY4137 increased transmembrane currents of CFTR-expressing oocytes. Na2S had no effect on native, non-injected oocytes. The effect of Na2S was blocked by the CFTR inhibitor CFTR_inh172, the adenylyl cyclase inhibitor MDL 12330A, and the protein kinase A antagonist cAMPS-Rp. Na2S potentiated CFTR stimulation by forskolin, but not that by IBMX. Na2S enhanced CFTR stimulation by membrane-permeable 8Br-cAMP under inhibition of adenylyl cyclase-mediated cAMP production by MDL 12330A. These data indicate that H2S activates CFTR in Xenopus oocytes by inhibiting phosphodiesterase activity and subsequent stimulation of CFTR by cAMP-dependent protein kinase A. In epithelia, an increased CFTR activity may correspond to a pro-secretory response to H2S which may be endogenously produced by the epithelium or H2S-generating microflora.

The ability to breathe air represents a fundamental step in vertebrate evolution that was accompanied by several anatomical and physiological adaptations. The morphology of the air-blood barrier is highly conserved within air-breathing vertebrates. It is formed by three different plies, which are represented by the alveolar epithelium, the basal lamina, and the endothelial layer. Besides these conserved morphological elements, another common feature of vertebrate lungs is that they contain a certain amount of fluid that covers the alveolar epithelium. The volume and composition of the alveolar fluid is regulated by transepithelial ion transport mechanisms expressed in alveolar epithelial cells. These transport mechanisms have been reviewed extensively. Therefore, the present review focuses on the properties and functional significance of the alveolar fluid. How does the fluid enter the alveoli? What is the fate of the fluid in the alveoli? What is the function of the alveolar fluid in the lungs? The review highlights the importance of the alveolar fluid, its volume and its composition. Maintenance of the fluid volume and composition within certain limits is critical to facilitate gas exchange. We propose that the alveolar fluid is an essential element of the air-blood barrier. Therefore, it is appropriate to refer to this barrier as being formed by four plies, namely (1) the thin fluid layer covering the apical membrane of the epithelial cells, (2) the epithelial cell layer, (3) the basal membrane, and (4) the endothelial cells.