Disorders of esophageal motor function and Lower Esophageal Sphincter (LES) competence affect more than one in ten adults over 40 and one in four adults over 60 years of age. Understanding of the mechanisms responsible for esophageal contraction and LES tone may be useful to understand normal function, and some of the changes associated with esophageal disease. Preliminary data suggest that esophageal contraction in response to acetylcholine (Ach) may be linked to muscarinic receptors activating intracellular phospholipases to induce phosphatidylcholine metabolism, production of diacylglycerol (DAG) and arachidonic acid (AA) and activation of a PKC dependent pathway. Resting LES tone may be associated with activity of a low molecular weight pancreatic-like (type 1) secreted phospholipase A2 (sPLA2) and production of arachidonic acid (AA), which is metabolized to prostaglandins and thromboxanes. These AA metabolites act on receptors linked to G-proteins to induce activation of phosphatidylinositol- and phosphatidylcholine-specific phospholipases, production of second messengers, activation of PKC and maintenance of contraction in LES circular muscle. The PKC isozymes mediating esophageal contraction and LES resting tone, however, are different. Esophageal contraction depends on the Ca++-insensitive PKC-epsilon, LES tone is associated with activation of the Ca++-dependent PKC-beta. Investigating the contractile mechanisms associated with and activated by these PKCs is necessary in order to understand normal esophageal and LES function. Because of the different Ca++-sensitivity of PKC-beta and PKC-epsilon some of the mechanisms upstream of PKC activation may be different in ESO and LES and some mechanisms activated by PKCs may be isozyme specific. In the next funding period it is therefore proposed to investigate: a) the cascade of events which depend upon agonist induced production of diacylglycerol and arachidonic acid, activation of PKC-epsilon and contraction of esophageal muscle. B) the events responsible for maintenance of sPLA2-induced production of AA and AA metabolites, and the mechanisms responsible for activation of G proteins, intracellular phospholipases, production of second messengers and maintenance of LES tone through a PKC-dependent pathway. These data will help in understanding contractile pathways in the normal esophagus and LES, and may provide a basis for better understanding of changes associated with some esophageal motor disorders.
Showing the most recent 10 out of 30 publications
