A reappraisal of the role of cyclic AMP in the physiological action of glucagon

Effects of the metabolic hormone glucagon can be physiological or supraphysiological, based on agonist concentration and the mediating cellular signal. The threshold concentration (TC) for activating the AC/cAMP signal pathway in liver is ≥100 pM. By contrast, mean plasma concentrations are around 20 - 45 pM, depending on the vascular bed. Accordingly, effects produced at TCs below 100 pM are physiological and mediated by cellular signal pathways other than AC/cAMP. Effects generated at concentrations above 100 pM are supraphysiological, often mediated by simultaneous activation of cAMP-independent and -dependent pathways. Physiological responses, and their established or implicated signal pathways, include stimulation of: glucose mobilization, fatty acid oxidation, and urea synthesis in liver (PLC/IP3/Ca2+/CaM); lipolysis in white adipose tissue and oxygen consumption in brown adipose of the rat but not in humans (PLC/IP3/Ca2+/CaM); renal potassium and phosphate excretion in rodents and GFR in humans (signal undetermined); and glucose utilization in rat heart (PI3K/akt). Supraphysiological responses involve the AC/cAMP pathway and include: enhanced stimulation of glucose mobilization and stimulation of urea synthesis in liver; further stimulation of white adipose lipolysis and stimulation of thermogenesis in brown adipose tissue; 3) stimulation of renal Cl- transport; and 4) increased rat heart contractility. The AC/cAMP pathway is likely recruited when plasma glucagon rises above 100 pM during periods of elevated metabolic stress and systemic glucose demand, such as in the early neonate or strenuously exercising adult. The current cAMP-centered model should therefore be reconsidered and replaced with one that places more emphasis on cAMP-independent pathways. DATA AVAILABILITY: No data were used in the research described in this article.