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. We have shown that contraction of esophageal (ESO) and LES circular muscle depends on distinct signal transduction pathways. ESO contraction in response to its endogenous neurotransmitter acetylcholine is mediated by protein kinase C (PKC)-dependent pathways, but the pathways activated by PKC to cause myosin phosphorylation and contraction in ESO are unknown. In contrast resting LES tone is associated with activity of a low molecular weight 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-specific and phosphatidylcholine-specific phospholipases, production of second messengers, activation of PKC and maintenance of sustained contraction. We have demonstrated that a pancreatic like (group I) sPLA2 contributes to LES tone, but other PLA2 (group II, V and X) may also be present. We now propose to: (A) examine PKC-activated contractile mechanism in ESO circular muscle and identify the proteins involved and the sequence of events initiated by PKC activation and resulting in myosin phosphorylation and contraction; (B) in LES circular muscle we will examine, 1) the role of group I and other sPLA2's and of arachidonic acid metabolilites in maintenance of LES tone, 2) PKC-activated contractile mechanisms. Similarly to ESO, the sequence of events initiated by PKC activation and resulting in myosin phosphorylation and LES contraction is unknown, 3) we will examine the PKC-dependent contractile pathways activated during initial contraction and during sustained contraction in response to AA metabolites, such as PGF2alpha and thromboxanes, which participate in maintenance of tone. Preliminary data indicate that a distinct PKC-dependent pathway may be activated during maintenance of tone, which is different from the pathway activated during the initial contractile response. 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.
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