PACAP Controls Adrenomedullary Catecholamine Secretion and Expression of Catecholamine Biosynthetic Enzymes at High Splanchnic Nerve Firing Rates Characteristic of Stress Transduction in Male Mice

Abstract

The neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) is a cotransmitter of acetylcholine at the adrenomedullary synapse, where autonomic regulation of hormone secretion occurs. We have previously reported that survival of prolonged metabolic stress in mice requires PACAP-dependent biosynthesis and secretion of adrenomedullary catecholamines (CAs). In the present experiments, we show that CA secretion evoked by direct high-frequency stimulation of the splanchnic nerve is abolished in native adrenal slices from male PACAP-deficient mice. Further, we demonstrate that PACAP is both necessary and sufficient for CA secretion ex vivo during stimulation protocols designed to mimic stress. In vivo, up-regulation of transcripts encoding adrenomedullary CA-synthesizing enzymes (tyrosine hydroxylase, phenylethanolamine N-methyltransferase) in response to both psychogenic and metabolic stressors (restraint and hypoglycemia) is PACAP-dependent. Stressor-induced alteration of the adrenomedullary secretory cocktail also appears to require PACAP, because up-regulation of galanin mRNA is abrogated in male PACAP-deficient mice. We further show that hypoglycemia-induced corticosterone secretion is not PACAP-dependent, ruling out the possibility that glucocorticoids are the main mediators of the aforementioned effects. Instead, experiments with bovine chromaffin cells suggest that PACAP acts directly at the level of the adrenal medulla. By integrating prolonged CA secretion, expression of biosynthetic enzymes and production of modulatory neuropeptides such as galanin, PACAP is crucial for adrenomedullary function. Importantly, our results show that PACAP is the dominant adrenomedullary neurotransmitter during conditions of enhanced secretory demand.

Pituitary Adenylate Cyclase Activating Polypeptide in Stress-Related Disorders: Data Convergence from Animal and Human Studies

“…Congruently, PACAP is colocalized with acetylcholine in abdominal preganglionic splanchnic nerve terminal terminals innervating the adrenal medulla for epinephrine release. PACAP application increases the excitability of adrenal chromaffin cells (36), and enhances the synthesis and release of adrenal catacholamines (9, 37, 38). Conversely, PACAP knockout mice exhibit disrupted catecholamine release patterns from splanchnic nerve activation and during chronic stress exposure (31, 37), which in aggregate suggest that PACAP is widely distributed throughout the HPA and sympathetic nervous system and is one of the principal facilitators of the endocrine and neuronal responses to stressful challenges.…”

Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats

“…This activation is mediated by indirect reflex excitation of the splanchnic nerve, which evokes large increases in catecholamine secretion (resulting in up to 70% of epinephrine content depletion) (47) accompanied by activation of TH enzyme and compensatory catecholamine biosynthesis in the adrenal medulla to maintain cellular catecholamine levels constant (41). As an index of catecholamine biosynthesis, we quantified changes in adrenal TH mRNA (25).…”

Nickel suppresses the PACAP-induced increase in guinea pig cardiac neuron excitability

“…The PACAP peptide amino acid sequence is highly conserved, and the action of PACAP is tissue specific dependent on the activation of the different isoforms of the seven transmembrane G proteincoupled PACAP-selective PAC 1 receptor (Adcyap1r1) and/or the vasoactive intestinal peptide (VPAC) receptors (2,4,20,45,54). PACAP/PAC 1 receptor signaling modulates synaptic transmission and plasticity via pre-and postsynaptic mechanisms, and these effects have been shown to be critically important in central stress responses, peripheral sensory and autonomic function, and maintenance of physiological homeostasis (9,18,19,21,25,31,32,40,41,47,49,54).We previously identified colocalization of PACAP with acetylcholine in cholinergic parasympathetic preganglionic terminals innervating guinea pig cardiac neurons (5, 6) and demonstrated that both endogenously released and exogenously applied PACAP significantly increases cardiac neuron excitability through PAC 1 receptor activation (5,22,35,49). Cardiac neurons are more readily accessible than CNS neurons for experimental manipulations and accordingly, we have used these cells to further our understanding of cellular PAC 1 receptor signaling mechanisms.…”

“…The PACAP peptide amino acid sequence is highly conserved, and the action of PACAP is tissue specific dependent on the activation of the different isoforms of the seven transmembrane G proteincoupled PACAP-selective PAC 1 receptor (Adcyap1r1) and/or the vasoactive intestinal peptide (VPAC) receptors (2,4,20,45,54). PACAP/PAC 1 receptor signaling modulates synaptic transmission and plasticity via pre-and postsynaptic mechanisms, and these effects have been shown to be critically important in central stress responses, peripheral sensory and autonomic function, and maintenance of physiological homeostasis (9,18,19,21,25,31,32,40,41,47,49,54).…”

“…PACAP/PAC 1 receptor signaling modulates synaptic transmission and plasticity via pre-and postsynaptic mechanisms, and these effects have been shown to be critically important in central stress responses, peripheral sensory and autonomic function, and maintenance of physiological homeostasis (9,18,19,21,25,31,32,40,41,47,49,54).…”