The purpose of these investigations is to examine the mechanisms of pancreatic exocrine secretion in human and animals models, in light of the novel concept of regulatory utility of the coupled synthesis and hydrolysis of cyclic nucleotides. The metabolic flux of cyclic nucleotides, generated by interdependent reactions catalyzed by cyclase(s) and phosphodiesterase(s), is proposed to constitute a biochemical process integral to excitation/secretion coupling, contrasting with the traditional hypothesis that the influence of cyclic nucleotides is mediated by an increase in their cellular content. A new technology designed to monitor the metabolic flux of cyclic nucleotides in intact cells is based on the principle that phosphodiesterase hydrolysis of cyclic nucleotides results in the incorporation of an atom of 18-0 derived from [18-0]water into the Alpha-phosphoryl of the 5'-nucleotide product. Using this analytical methodology as well as new and sensitive procedures for measurement of Ca+2 release and inositol triphosphate generation, processes thought to participate in excitation/secretion coupling in exocrine pancreas, we propose to examine the following: 1) whether endogenous mammalian peptides representing the two definable classes of pancreatic secretagogues, e.g. secretin and cholecystokinin, selectively activate cAMP or cGMP metabolic flux; 2) whether stimulus-promoted acceleration of cyclic nucleotide metabolic fluxes satisfies fundamental criteria for a cause and effect relationship in excitation/secretion coupling; 3) the characterization of """"""""excitatory"""""""" and """"""""adaptive"""""""" cellular cyclic nucleotide metabolic compartments proposed to be involved in stimulus/secretion coupling and cell response modulation, respectively; 4) the interrelationship of cyclic nucleotide metabolic flux, polyphosphoinositide hydrolysis/inositol triphosphate generation, and Ca+2 release in human and guinea pig models of pancreatic exocrine secretion.
| Deeg, M A; Graeff, R M; Walseth, T F et al. (1988) A Ca2+-linked increase in coupled cAMP synthesis and hydrolysis is an early event in cholinergic and beta-adrenergic stimulation of parotid secretion. Proc Natl Acad Sci U S A 85:7867-71 |
