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 wildtype 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. T he adrenal medulla has been used extensively as a model for understanding basic features of neurotransmission and transsynaptic regulation, because of the simplicity of its synaptic inputs and the physiological importance and ease of measurement of catecholamine secretion as a final output (1). Recently, the adrenomedullary synapse has been the focus of analysis of the functional meaning of classical neurotransmitter and neuropeptide coexpression and corelease at mammalian synapses (2). Acetylcholine is the primary neurotransmitter mediating catecholamine secretion from the adrenal medulla (3). A second noncholinergic neurotransmitter also is thought to be involved in sympathoadrenal function because acetylcholine, or cholinergic agonists alone, cannot mimic the prolonged secretion and robust stimulation of catecholamine biosynthesis elicited by electrical stimulation of the splanchnic innervation of the adrenal medulla (4-7). It has been proposed that pituitary adenylate cyclaseactivating peptide (PACAP) or a PACAP-related neuropeptide acts as a cotransmitter with acetylcholine at the adrenomedullary synapse, based on neuroanatomical evidence obtained in v...

Pituitary Adenylate Cyclase-activating Peptide (PACAP) Recruits Low Voltage-activated T-type Calcium Influx under Acute Sympathetic Stimulation in Mouse Adrenal Chromaffin Cells

“…Previous studies have indicated that PACAP acts as a primary neurotransmitter at the splanchnicadrenal synapse under the stress response (15)(16)(17). Indeed, PACAP-null mice have been shown to not mount a stress response to insulin shock and to perish under this challenge (17). Despite this physiologically important role, relatively little is known of how PACAP stimulation elicits the initial catecholamine burst under acute sympathetic stimulation.…”

“…Thus, chromaffin cells form a critical element of the acute sympathetic stress response. Previous studies have indicated that PACAP acts as a primary neurotransmitter at the splanchnicadrenal synapse under the stress response (15)(16)(17). Indeed, PACAP-null mice have been shown to not mount a stress response to insulin shock and to perish under this challenge (17).…”

“…Thus, a non-cholinergic splanchnic-adrenal transmitter was predicted to elicit chromaffin cell catecholamine release under elevated stimulation (14). Previous work identified the peptidergic transmitter pituitary adenylate cyclase-activating peptide (PACAP) 2 as a likely candidate (15)(16)(17) to substitute for cholinergic adrenal stimulation under the sympathoadrenal stress response.…”

Direct cAMP Signaling through G-Protein-Coupled Receptors Mediates Growth Cone Attraction Induced by Pituitary Adenylate Cyclase-Activating Polypeptide

“…It seems reasonable that an autocrine loop would likely promote the rate of neurite extension; potentially, asymmetric inhibition of autocrine PACAP-PAC1 interactions at the growth cone could also influence the direction of growth cone extension. Finally, local PACAP-PAC1 interaction at synapses (Otto et al, 1999(Otto et al, , 2001Roberto and Brunelli, 2000;Hamelink et al, 2002) could be involved in the final stages of guidance or in structural plasticity (i.e., new neurite sprouts could be elicited and attracted to establish more connections). The possible effects of PACAP on growth cone guidance and other aspects of development will undoubtedly provide interesting avenues for future studies.…”

Endogenous PACAP acts as a stress response peptide to protect cerebellar neurons from ethanol or oxidative insult

“…Transgenic animals used in this study were wild type and PACAP knock-out C57BL/6 mice generated as previously reported [10]. PACAP-deficient mice were obtained from mixed strain C57BL/6 × 129/SvJ mice backcrossed onto the C57BL/6 background for seven generations.…”