A glucagon fragment is responsible for the inhibition of the liver Ca2+ pump by glucagon

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Abstract
Glucagon specifically inhibits the Ca2+ pump in liver plasma membranes independently of adenylate cyclase activation1. However, this inhibition is only observed at high concentrations of glucagon (Ki = 0.7 µM). Moreover, in the presence of bacitracin, an inhibitor of glucagon degradation2, the Ca2+ pump is no longer sensitive to glucagon3. These findings suggest that a fragment of glucagon might be the true effector of the liver Ca2+ pump. Pairs of basic amino acids are recognized as potential cleavage sites in post-translational processing of peptide hormones4–6. The glucagon molecule includes a dibasic doublet (Arg 17–Arg 18). Therefore, we have examined the action of glucagon( 19–29) on the liver Ca2+ pump. This peptide was obtained from glucagon by tryptic cleavage and separated by reverse-phase high-performance liquid chromatography. We found that glucagon( 19–29), which is totally ineffective in activating adenylate cyclase, inhibited both the Ca2+-activated and Mg2+-dependent ATPase activity ((Ca2+-Mg2+) ATPase) and Ca2+ transport in liver plasma membranes with an efficiency 1,000-fold higher than that of glucagon. Glucagon(l–21) was completely inactive; glucagon( 18–29) and glucagon(22–29) acted only as partial agonists of glucagon( 19–29). These results indicate that glucagon( 19–29), obtained by proteolytic cleavage of glucagon, is likely to be the active peptide involved in the inhibition of the liver Ca2+ pump. We suggest that glucagon may be a precursor of at least one biologically active peptide.