Activation of separate calcium and A-kinase-dependent pathways by ACTH

Although cAMP has long been regarded as the primary intracellular messenger for ACTH-stimulated cortisol secretion, a requirement for Ca2+ is well established. However, a specific mechanism which couples ACTH receptor activation to increased intracellular calcium concentration in the adrenal cortical cell has not been elucidated. Here, we present evidence for a specific model in which ACTH at picomolar concentrations induces cAMP which acts through kinase-dependent and independent pathways to stimulate cortisol secretion. Along one of these pathways, cAMP acts directly to depolarize cells by inhibition of a specific non-inactivating K+ channel (I(AC)). This model provides a specific mechanism whereby cAMP-mediated inhibition of I(AC) is tightly coupled to depolarization-dependent Ca2+ entry and cortisol secretion. Ca2+ and cAMP are dual second messengers in the ACTH signalling pathway that are linked through I(AC) K+ channels.