Secretin receptor activity in rat gastric glands. Binding studies, cAMP generation and pharmacology.
We measured 125I-secretin binding to membranes prepared from rat fundic glands and compared the abilities of natural and synthetic secretin (SN) analogs to inhibit 125I-secretin binding and to activate the cAMP generating system in glandular and subcellular preparations from the fundus and antrum. The natural peptides structurally related to porcine secretin (pSN) included: chicken secretin (cSN), vasoactive intestinal peptide (VIP), porcine peptide with N-terminal histidine and C-terminal isoleucine amide (PHI), helodermin, growth hormone releasing factors isolated from the rat hypothalamus (rhGRF-43, rhGRF-29) or from a human pancreatic tumour (hpGRF-40). These peptides inhibited the binding of 125I-secretin to rat fundic membranes: pSN greater than cSN greater than PHI, VIP and activated the cAMP generating system in fundic glands, according to the following order of potency; pSN greater than cSN greater than PHI, VIP greater than rhGRF-29 greater than rhGRF-43. Porcine peptide with N-terminal tyrosine and C-terminal tyrosine (PYY), GIP, SOM and hpGRF-40 were inactive. Structural requirements for secretin receptor activity were evaluated with four synthetic secretin analogs corresponding to porcine secretin substituted at the N-terminal end by sequence portion of VIP, GIP, GLU and SOM: Ala4-Val5-SN(VIP-SN); Tyr1-Ala2-Glu3-SN (GIP-SN); Gln3-SN (GLU-SN) and Phe1-Phe1-Trp3-Lys4-SN (SOM-SN). The relative potencies of the analogs in fundic and antral preparations were: pSN greater than VIP-SN greater than VIP, GIP-SN greater than GLU-SN greater than SOM-SN for 125I-secretin displacement and cAMP production (glandular cAMP generation and adenylate cyclase activation).(ABSTRACT TRUNCATED AT 250 WORDS)
D000262:Adenylyl Cyclases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis*; D005748:Gastric Fundus / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D011706:Pyloric Antrum / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D012633:Secretin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; C029937:secretin receptor; D012633:Secretin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases