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

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 (K_i = 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 hormones^4–6. 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.