Several conclusions about PACAP involvement in stress transduction and neuroprotection during stress can be inferred from the data obtained so far, both from our own laboratory and that of others. However, several questions remain to be addressed, as enumerated below, before the role of PACAP in these functions emerges with sufficient clarity to exploit therapeutically in traumatic brain injury, post-traumatic stress disorder and other anxiety disorders.
First, PACAP regulates stress hormone biosynthesis in adrenal gland via up-regulation of at least two enzymes involved in epinephrine biosynthesis, TH and PNMT. Second, PACAP acts at the level of the hypothalamus to control induction, though not basal levels, of CRH mRNA. Third, PACAP control of stress hormone biosynthesis appears to be specialized for prolonged
stress axis activation. Fourth, at least in its effects on the chromaffin cell of the adrenal medulla, and possibility also in cerebrocortical neurons, PACAP utilizes a novel ERK-mediated cAMP-dependent/PKA-dependent signaling pathway to activate a ‘stress response transcriptome’ that includes other neuropeptides, neuroprotective factors, and prohormone convertases. Finally, it is noteworthy that PACAP modulation of stress response in the brain may extend even beyond the HPA and HSA axes. May and colleagues have characterized PACAP induction of a cohort of neuropeptides in cultured post-ganglionic sympathetic neurons in culture [14
]. These results imply an action of PACAP to mediate stress responses specific to the sympathetic nervous system (SNS) although these have not yet been investigated in vivo despite the critical role of SNS activation in acute and chronic homeostatic and allostatic responses to a wide range of stressful stimuli [27
]. Hammack and colleagues have observed that PACAP expression in the bed nucleus of the stria terminalis is greatly enhanced by prolonged stress, and have postulated a potential anxiogenic role for PACAP in the limbic system [55
]. The effects of PACAP at these different levels of stress response are summarized in .
PACAP is a master regulator of stress circuits in brain and periphery
As a master regulator of stress responses throughout the neuroaxis, PACAP may represent only a ‘jack of all trades’ in mediating neuroprotective, neurotransmission, and gating functions in hypothalamic, hippocampal, amygdalar, and peripheral nervous transduction of homeostatic and allostatic stress responses. GAL, CRH, adenosine, and other neuropeptides may play more specialized roles at particular neuroanatomical locations and under specific stress conditions. PACAP does, however, deserve further attention as a major multi-level stress regulator whose modulation could affect deleterious sustained stress leaving intact the acute (fight or flight) stress response helpful for survival.
In summary, PACAP is paradigmatic as a neuropeptide regulator in stress, and some more general conclusions can also be drawn about microarray analysis of neuropeptide-regulated genes from the accumulating information about PACAP signaling. Microarray analysis reveals--in an unbiased way—gene targets related to mechanisms, biomarkers, and potential drug targets for stress-related disease. These may overlap, and may also function to reinforce each other in translational and reverse-translational approaches to understanding and treatment of stress disorders (). Signaling pathways activated in stress may be dissected pharmacologically to allow manipulation of individual components, e.g. neuroprotection, stress hormone biosynthesis, neurotrophin production. Finally, deciding when neuropeptide agonists or antagonists should be sought as stress management therapeutics remains a key question, and one that can be addressed in part by microarray analysis of neuropeptide signaling to the nucleus in a variety of physiological contexts.
Gene expression analysis reveals mechanism, biomarkers, and therapeutic targets in stress