RECEPTOR REGULATED CALCIUM ENTRY IN EXOCRINE SECRETION

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The overall aim of this research is further understanding of the cellular mechanisms involved in the initiation and control of exocrine secretion. The stimulation of exocrine secretory activity by various hormones and neurotransmitters is known to involve increases in intracellular calcium ion (Ca2+) concentrations, increases that generally result partly from an initial mobilization of intracellular Ca2+ pools and partly from an enhanced entry of Ca2+ across the plasma membrane. It has been established that such responses are also associated with the increased turnover of membrane phosphoinositides, but the relationship between the metabolism of these membrane phospholipids and changes in membrane calcium permeability are unknown. Current models emphasize the possible significance of the inositol (poly) phosphates, produced by phosphoinositide breakdown, in inducing the receptor-activated increase in plasma membrane calcium permeability. In particular, an essential "permissive" role has been proposed for inositol (1,4,5) trisphosphate (I(1,4,5)P3), possibly in association with inositol (1,3,4,5) tetrakisphosphate (I(1,3,4,5)P4). This permissive role of I(1,4,5)P32+ is believed to be associated with its known ability to mobilize intracellular Ca2+ stores. However, preliminary studies on muscarinic receptor- activated increases in intracellular Ca2+ concentration in the avian nasal gland have failed to detect any mobilization of intracellular Ca2+ in this tissue. This suggests that current models may need to be modified, perhaps by considering other possible actions of I(1,4,5)P3 to account for its apparent permissive role, or by considering the possibility of I(1,3,4,5)P being directly capable of increasing activating Ca2+ influx in this tissue. This problem will be studied by investigating the relationships between inositol phosphate production and increases in intracellular Ca2+ concentration in isolated cells using anion- exchange chromatography and fluorimetric techniques. In addition, the direct effects of exogenous inositol phosphates on Ca2+ entry will be examined in single isolated cells by a technique combining whole-cell dialysis, using a patch-pipette, and simultaneous microfluorimetry of Ca2+ -dependent indo-1 fluorescence.