Challenge of intact hepatocytes with amylin only succeeded in elevating intracellular cyclic AMP levels and activating phosphorylase in the presence of the cAMP phosphodiesterase inhibitor IBMX. Both amylin and CGRP similarly activated adenylate cyclase, around 5‐fold, although ∼ 400‐fold higher levels of amylin were required to elicit half maximal activation. Amylin activated adenylate cyclase though apparently simple Michaelin kinetics whereas CGRP elicited activation by kinetics indicative of apparent negative co‐operativity. Use of the antagonist CGPP(8–37) showed that both CGRP and amylin activated hepatocyte adenylate cyclase through a common receptor by a mnemonical mechanism where it was proposed that the receptor co‐existed in interconvertible high and low affinity states for CGRP. It is suggested that this model may serve as a paradigm for G‐protein linked receptors in general. Amylin failed to both stimulate inositol phospholipid metabolism in hepatocytes and to elicit the desensitization of glucagon‐stimulated adenylate cyclase. Amylin did, however, elicit the phosphorylation of the inhibitory guanine nucleotide regulatory protein Gi‐2 in hepatocytes and prevented the action of insulin in reducing the level of phosphorylation of this G‐protein.
- Adenylate cyclase
- Negative co-operativity
- Cyclic AMP
- Guanine nucleotide regulatory protein