INTERACTION BETWEEN SIGNAL-TRANSDUCTION PATHWAYS CONTRIBUTING TO GALLBLADDER TONIC CONTRACTION

Muscle strips were used to study the mechanisms that generate cat gall bladder tone. Strontium substitution for calcium and the protein kinas e C (PKC) inhibitor H-7 abolished the tone, whereas the calmodulin ant agonist W-7 had no effect, suggesting that tone depends on intracellul ar calcium release and the PKC pathway. Basal levels of diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (IP3) were higher in gallbladd er muscle than in esophageal muscle, which does not maintain tone. The se data suggest that IP3 might interact with DAG to activate PKC durin g tonic contraction. This interaction was demonstrated in single cells in which a low dose of IP3 potentiated DAG and the potentiation was b locked by H-7. Furthermore, low doses of IP3 induced contraction, whic h was blocked by H-7 and unaffected by the calmodulin antagonist CGS-9 343B; high doses of IP3 were unaffected by H-7 but were blocked by CGS -9343B; DAG-induced contraction was blocked by activated calmodulin. W e conclude that 1) the synergistic action of DAG and IP3-calcium relea se, which further activates PKC, might be responsible for gallbladder tone and 2) activated calmodulin appears to inhibit the effect of PKC.