Cholecystokinin regulates expression of Y2 receptors in vagal afferent neurons serving the stomach.
The intestinal hormones CCK and PYY3-36 inhibit gastric emptying and food intake via vagal afferent neurons. Here we report that CCK regulates the expression of Y2R, at which PYY3-36 acts. In nodose ganglia from rats fasted up to 48 h, there was a fivefold decrease of Y2R mRNA compared with rats fed ad libitum; Y2R mRNA in fasted rats was increased by administration of CCK, and by refeeding through a mechanism sensitive to the CCK1R antagonist lorglumide. Antibodies to Y2R revealed expression in both neurons and satellite cells; most of the former (89 +/- 4%) also expressed CCK1R. With fasting there was loss of Y2R immunoreactivity in CCK1R-expressing neurons many of which projected to the stomach, but not in satellite cells or neurons projecting to the ileum or proximal colon. Expression of a Y2R promoter-luciferase reporter (Y2R-luc) in cultured vagal afferent neurons was increased in response to CCK by 12.3 +/- 0.1-fold and by phorbol ester (16.2 +/- 0.4-fold); the response to both was abolished by the protein kinase C inhibitor Ro-32,0432. PYY3-36 stimulated CREB phosphorylation in rat nodose neurons after priming with CCK; in wild-type mice PYY3-36 increased Fos labeling in brainstem neurons but in mice null for CCK1R this response was abolished. Thus Y2R is expressed by functionally distinct subsets of nodose ganglion neurons projecting to the stomach and ileum/colon; in the former expression is dependent on stimulation by CCK, and there is evidence that PYY3-36 effects on vagal afferent neurons are CCK dependent.
Burdyga
Galina
G
Physiological Laboratory, School of Biomedical Sciences and School of Preclinical Veterinary Science, University of Liverpool, Liverpool, United Kingdom.
de Lartigue
Guillaume
G
Raybould
Helen E
HE
Morris
Richard
R
Dimaline
Rod
R
Varro
Andrea
A
Thompson
David G
DG
Dockray
Graham J
GJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D002766:Cholecystokinin / Q000494:pharmacology*; D005215:Fasting / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009475:Neurons, Afferent / Q000187:drug effects*; D009620:Nodose Ganglion / Q000166:cytology; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D011377:Proglumide / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D043886:Receptor, Cholecystokinin A / Q000172:deficiency; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D012528:Satiety Response / Q000187:drug effects / Q000502:physiology; D013270:Stomach / Q000294:innervation*; D014630:Vagus Nerve / Q000166:cytology*
D002756:Cholagogues and Choleretics; D006727:Hormone Antagonists; D016761:Oncogene Proteins v-fos; D012333:RNA, Messenger; D043886:Receptor, Cholecystokinin A; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D002766:Cholecystokinin; D011377:Proglumide; C048181:lorglumide