Regulation of neurosecretory habituation in PC12 cells: parallel pathways used by cAMP and calcium.

Habituation of norepinephrine secretion in PC12 cells serves as a model for understanding the molecular mechanisms of simple memory processes in neurons. Elevation of intracellular cAMP levels by incubation with N-ethylcarboxamidoadenosine (NECA) or forskolin increased norepinephrine secretion in response to depolarization by high potassium or stimulation with acetylcholine. The extent to which cAMP altered norepinephrine secretion was dependent on the timing of its elevation, and it also altered the rate of habituation under certain conditions. However, cAMP increased norepinephrine secretion by a pathway distinct from that governing internal calcium levels, which correlates with habituation in the absence of elevated cAMP. An inverse correlation was found between the ability of calcium to lower NECA-induced cAMP levels and the ability of calcium to cause norepinephrine secretion. A model is proposed in which a single calcium-dependent pathway modulates both norepinephrine secretion and cAMP metabolism.