title: Pituitary adenylate cyclase-activating polypeptide is a sympathoadrenal neurotransmitter involved in catecholamine regulation and glucohomeostasis.
abstract: The adrenal gland is important for homeostatic responses to metabolic stress: hypoglycemia stimulates the splanchnic nerve, epinephrine is released from adrenomedullary chromaffin cells, and compensatory glucogenesis ensues. Acetylcholine is the primary neurotransmitter mediating catecholamine secretion from the adrenal medulla. Accumulating evidence suggests that a secretin-related neuropeptide also may function as a transmitter at the adrenomedullary synapse. Costaining with highly specific antibodies against the secretin-related neuropeptide pituitary adenylate cyclase-activating peptide (PACAP) and the vesicular acetylcholine transporter (VAChT) revealed that PACAP is found in nerve terminals at all mouse adrenomedullary cholinergic synapses. Mice with a targeted deletion of the PACAP gene had otherwise normal cholinergic innervation and morphology of the adrenal medulla, normal adrenal catecholamine and blood glucose levels, and an intact initial catecholamine secretory response to insulin-induced hypoglycemia. However, insulin-induced hypoglycemia was more profound and longer-lasting in PACAP knock-outs, and was associated with a dose-related lethality absent in wild-type mice. Failure of PACAP-deficient mice to adequately counterregulate plasma glucose levels could be accounted for by impaired long-term secretion of epinephrine, secondary to a lack of induction of tyrosine hydroxylase, normally occurring after insulin hypoglycemia in wild-type mice, and a consequent depletion of adrenomedullary epinephrine stores. Thus, PACAP is needed to couple epinephrine biosynthesis to secretion during metabolic stress. PACAP appears to function as an "emergency response" cotransmitter in the sympathoadrenal axis, where the primary secretory response is controlled by a classical neurotransmitter but sustained under paraphysiological conditions by a neuropeptide.
authors.affiliation: Sections on Molecular Neuroscience and Neural Gene Expression, Laboratory of Cellular and Molecular Regulation, and Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, MD 20892, USA.
authors.forename: Carol
authors.initials: C
authors.lastname: Hamelink
authors.forename: Olga
authors.initials: O
authors.lastname: Tjurmina
authors.forename: Ruslan
authors.initials: R
authors.lastname: Damadzic
authors.forename: W Scott
authors.initials: WS
authors.lastname: Young
authors.forename: Eberhard
authors.initials: E
authors.lastname: Weihe
authors.forename: Hyeon-Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Lee E
authors.initials: LE
authors.lastname: Eiden
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002395:Catecholamines / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000378:metabolism; D017353:Gene Deletion; D005938:Glucocorticoids / Q000378:metabolism; D005947:Glucose / Q000502:physiology*; D006706:Homeostasis; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008957:Models, Genetic; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: C495402:Adcyap1 protein, mouse; D001786:Blood Glucose; D002395:Catecholamines; D018076:DNA, Complementary; D005938:Glucocorticoids; D007328:Insulin; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D014446:Tyrosine 3-Monooxygenase; D005947:Glucose; D004837:Epinephrine