Mechanism of glucagon activation of adenylate cyclase in the presence of Mn2+

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Abstract
For a variety of ligand states, adenylate cyclase activity in the presence of Mn2+ was greater than with Mg2+. Trypsin treatment of intact hepatocytes, under conditions which destroy cell surface glucagon receptors, led to a first order loss of glucagon-stimulated adenylate cyclase activity in isolated membranes assayed in the presence of Mn2+ whether or not GTP (100 μM) was present in the assays. Arrhenius plots of basal activity exhibited a break at around 22°C, those with NaF were linear and those with glucagon ± GTP (100 μM) were biphasic with a break at around 28°C. It is suggested that Mn2+ perturbs the coupling interaction between the glucagon receptor and catalytic unit of adenylate cyclase at the level of the guanine nucleotide regulatory protein. This appears to take the form of Mn2+ preventing GTP from initiating glucagon's activation of adenylate cyclase through a collision coupling mechanism.