Pituitary adenylate cyclase-activating polypeptide type I receptors mediate cyclic AMP-dependent enhancement of neuronal acetylcholine sensitivity.
Nicotinic acetylcholine (ACh) receptors (AChRs) on ciliary ganglion neurons are positively regulated by elevated cAMP levels. Vasoactive intestinal peptide (VIP) can act as a first messenger in the regulation, because application of 1 microM VIP rapidly increases both neuronal cAMP levels and ACh sensitivity. We now report that high affinity receptors for a close VIP relative, pituitary adenylate cyclase-activating polypeptide (PACAP), are present on ciliary ganglion neurons and mediate the cAMP-dependent modulation of AChRs. Consistent with the presence of PACAP type I receptors, binding studies revealed sites on the neurons having approximately 1000-fold higher affinity for the 38- and 27-amino acid forms of PACAP than for VIP, and cAMP radio-immunoassays demonstrated that PACAP38 and PACAP27 are approximately 600-fold more potent agonists for mobilizing neuronal cAMP than is VIP. In accord with their higher affinity and potency, PACAP38 and -27 (both at 10 nM) increased neuronal ACh sensitivity by approximately 50% within 10 min, whereas VIP at the same low concentration was ineffective. The increased ACh sensitivity induced by 10 nM PACAP38 or PACAP27 or 1 microM VIP depends on coincident increases in cAMP levels, because treatment of neurons with adenylate cyclase inhibitors blocked both effects. The findings demonstrate the presence of functional PACAP type I receptors on ciliary ganglion neurons that preferentially recognize PACAP38 and -27 over VIP and act via adenylate cyclase to initiate cAMP-dependent enhancement of AChR function. Finally, we detected PACAP38-like material in ciliary ganglia, suggesting a role for the peptide in modulating neuronal AChRs in vivo.
Margiotta
J F
JF
Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York 10029, USA.
Pardi
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D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D002642:Chick Embryo; D000242:Cyclic AMP / Q000096:biosynthesis / Q000502:physiology*; D005724:Ganglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009479:Neuropeptides / Q000494:pharmacology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone / Q000819:agonists / Q000502:physiology*
D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D011979:Receptors, Pituitary Hormone; D000242:Cyclic AMP; D000109:Acetylcholine