Pharmacology of Airway Goblet Cell Mucin Release

Abstract

Abstract. Airway mucus hypersecretion is one of the major clinical manifestations of patients suffering from various pulmonary diseases. However, no drugs are yet available to control airway mucus hypersecretion. For the past 15 years, a plethora of information has amassed with regard to the pharmacology of airway goblet cell mucin secretion using various primary cell culture systems. The recent discovery of various MUC genes has also greatly stimulated research in this field. Nevertheless, the heterogeneity of the oligosaccharide structure of mucin molecules makes it extremely difficult to assess the significance of the information derived from the pharmacological studies. Therefore, it seems crucially important to understand the roles of individual mucins in conjunction with normal airway physiology and pathology, which should be the future research directions necessary for studying airway goblet cell mucin pharmacology.

nPKCε, a P2Y2-R downstream effector in regulated mucin secretion from airway goblet cells

“…Studies using apical purinergic agonists to stimulate mucin release in a wide variety of human (12,30) and animal (16,31) experimental models have demonstrated that ATP and UTP stimulate mucin secretion, most likely via an apically localized purinoceptor P2Y 2 -R. In addition to these pharmacological indications, P2Y 2 -R mRNA has been identified in SPOC1 cell (3) and in hamster (32) airway goblet cell models. Though it was intended primarily as a control in the present study, our results showing a major loss of ATP␥S-stimulated mucin secretion in P2Y 2 -R KO mouse tracheas (Fig.…”

“…Activated P2Y-Rs couple via G␣ q to phospholipase C-␤ to cause the production of the cellular messengers IP 3 and DAG from PIP 2 , leading to Ca 2ϩ mobilization and PKC activation (62). Pharmacological studies conducted over many years with ionomycin and PMA in goblet cell models have suggested consistently that Ca 2ϩ and PKC are important in regulated mucin secretion (16,31), but mechanistic details remain elusive. Previously, we showed that nPKC␦ activation in SPOC1 cells correlates positively with regulated mucin secretion, a result that identified this isoform as a potential P2Y 2 -R downstream effector (1).…”

“…Little specific information is available regarding effector molecules regulating this pathway downstream of messenger production in goblet cells. In this paper, we focus on identification of the PKC isoform(s) participating in agonist-induced mucin release.The members of the PKC family have been implicated in signaling pathways of a wide variety of cellular processes, including regulated mucin secretion (15,17,30,31). Previously, we have shown that membrane-associated PKC activity is enhanced by P2Y 2 agonists and PMA in the mucin-secreting SPOC1 cell line (1), indicating a likely PKC participation in regulated mucin secretion.…”

“…P2Y 2 -R activation by agonist elicits a coupling with PLC via G q , production of the primary intracellular messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP 3 ) from phosphatidylinositol-4,5-bisphosphate (PIP 2 ), followed by activation of protein kinase C (PKC) and mobilization of Ca 2ϩ (62). Pharmacological studies in goblet cells have shown that mucin secretion can be stimulated via intracellular messenger pathways by the DAG mimic phorbol-1,2-myristate-13-acetate (PMA) (15,17,30,31), by IP 3 (52), and by the Ca 2ϩ -mobilizing agents ionomycin and thapsigargin (15,30,51). Each of these signaling molecules is thought to activate or modulate a series of protein-mediated events, ultimately to elicit exocytosis of mucin secretory granules.…”

“…15). Two such mediators, the nucleotides ATP and UTP, appear to be major agonists in goblet cell mucin secretion acting via P2Y 2 purinoceptors (P2Y 2 -Rs) (15,17,31,62). P2Y 2 -R activation by agonist elicits a coupling with PLC via G q , production of the primary intracellular messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP 3 ) from phosphatidylinositol-4,5-bisphosphate (PIP 2 ), followed by activation of protein kinase C (PKC) and mobilization of Ca 2ϩ (62).…”