PACAP: a master regulator of neuroendocrine stress circuits and the cellular stress response.

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is released from stress-transducing neurons. It exerts postsynaptic effects required to complete the hypothalamo-pituitary-adrenocortical (HPA) and hypothalamo-sympatho-adrenal (HSA) circuits activated by psychogenic and metabolic stressors. Upon activation of these circuits, PACAP-responsive (in cell culture models) and PACAP-dependent (in vivo) transcriptomic responses in the adrenal gland, hypothalamus, and pituitary have been identified. Gene products produced in response circuits during stress include additional neuropeptides, neurotransmitter biosynthetic enzymes, and neuroprotective factors. Major portions of HPA and HSA stress responses are abolished in PACAP-deficient mice. This deficit occurs at the level of both the hypothalamus (HPA axis) and the adrenal medulla (HSA axis). PACAP-dependent transcriptional stress responses are conveyed through noncanonical cyclic AMP- and calcium-initiated signaling pathways within the HSA circuit. PACAP transcriptional regulation of the HPA axis, in the hypothalamus, is likely to be mediated via canonical cyclic AMP signaling through protein kinase A.