CCK-JMV-180: a peptide that distinguishes high-affinity cholecystokinin receptors from low-affinity cholecystokinin receptors.
When pancreatic acini are incubated with increasing concentrations of cholecystokinin octapeptide (CCK-8) the dose-response curve for stimulation of enzyme secretion increases, reaches a maximum and then decreases. The upstroke of the dose-response curve reflects occupation of high-affinity, stimulatory CCK receptors (Kd 69 pM), whereas the downstroke of the dose-response curve reflects occupation of low-affinity inhibitory CCK receptors (Kd 10 nM). In the present study, we used dispersed acini from rat pancreas to examine the effects of CCK-JMV-180, an analogue of the C-terminal heptapeptide of CCK (CCK-7) having the structure BOC-Tyr(SO3) Ahx-Gly-Trp-Ahx-Asp2 phenylethyl ester. CCK-JMV-180 inhibited binding of 125I-labelled CCK-8 to pancreatic acini. Computer analysis of the dose-inhibition curve indicated that CCK-JMV-180 interacted with both classes of CCK receptor and had a Kd of 2.2 nM for high-affinity CCK receptors and a Kd of 19 nM for low-affinity CCK receptors. Occupation of high-affinity CCK receptors by CCK-JMV-180 caused a 14-fold increase in amylase secretion, the same increase caused by occupation of these high-affinity receptors by CCK-7 or CCK-8. Occupation of low-affinity CCK receptors by CCK-JMV-180 did not alter amylase secretion, in contrast to occupation of these low-affinity receptors by CCK-7 or CCK-8, each of which caused inhibition of amylase secretion. Furthermore, occupation of the low-affinity CCK receptors by CCK-JMV-180 reversed the inhibition of amylase secretion caused by a supramaximal concentration of CCK-8. The present results indicate that CCK-JMV-180 interacts with high-affinity CCK receptors and with low-affinity CCK receptors, and has a functionally distinct action at each class of receptor: CCK-JMV-180 is an agonist at the high-affinity receptors and a competitive antagonist at the low-affinity receptors.
Stark
H A
HA
Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892.
Sharp
C M
CM
Sutliff
V E
VE
Martinez
J
J
Jensen
R T
RT
Gardner
J D
JD
D000681:Amylases / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D007700:Kinetics; D008297:Male; D010179:Pancreas / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000378:metabolism*; D012844:Sincalide / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D010446:Peptide Fragments; D011949:Receptors, Cholecystokinin; C058451:JMV 180; C025997:cholecystokinin (27-33); D000681:Amylases; D012844:Sincalide