Effects of Cholecystokinin (CCK)-JMV-180 on the CCK Receptors of Rabbit Pancreatic Acini and Gallbladder Smooth Muscle

Abstract

ABSTRACT-Effectsof cholecystokinin (CCK)-JMV-180, a CCK analog, on the CCK receptor functions of isolated rabbit pancreatic acini and gallbladder smooth muscle were studied. When the pancreatic acini were incubated with increasing concentrations of CCK-8, stimulation of amylase release reached a maximum at 3 nM and then declined with the increasing concentration of CCK-8. CCK-JMV-180 also caused a dosedependent amylase release stimulation, which plateaued and remained unchanged above 300 nM at about 50% of the maximal stimulation by CCK-8. CCK-JMV-180 above 100 nM caused a rightward shift of the downstroke of the dose-response curve for CCK-8 (pA2=7.5). In the gallbladder smooth muscle, CCK-8 caused a dose-dependent contraction, but CCK-JMV-180 totally lacked this property. Instead, CCK-JMV-180 caused a rightward shift of the dose-response curve for CCK-8 (pA2=7.9). These results suggest that CCK-JMV-180 distinguishes between the CCKA receptors associated with pancreatic exocrine secretion in the acini and those involved in contraction of the isolated gallbladder smooth muscle in rabbits.

Involvement of endogenous CCK and CCK1 receptors in colonic motor function

“…In line with these results, Moran et al (1994) suggested that CCK‐8 induces pyloric contraction and delays gastric emptying via interaction with receptors functionally similar to low‐affinity pancreatic receptors. Furthermore, similar results have been obtained with gallbladder smooth muscle from guinea‐pig and rabbit ( Maubach et al , 1991 ; Taniguchi et al , 1995 ), suggesting that the absence of high‐affinity CCK 1 receptors on gastrointestinal smooth muscle cells might be a general phenomenon, at least in rodents.…”

“…Although the nucleotide sequences of cloned cDNAs of CCK 1 receptors from pancreas and from gastric and gallbladder smooth muscle are identical ( De Weerth et al , 1993 ), their affinity states are different ( Maubach et al , 1991 ; Moran et al , 1994 ; Taniguchi et al , 1995 ; Varga et al , 1988 ; 1998; Kisfalvi et al , 2001 ) (Figure 6). The available evidence suggests that the CCK 1 receptor exists in both high‐ and low‐affinity states ( Bianchi et al , 1994 ; Rivard et al , 1994 ; Tsunoda & Owyang, 1995) and that CCK occupancy of these results in the initiation of different intracellular events and consequent biological responses.…”

“…Binding of the peptide to high‐affinity CCK 1 receptors leads to synchronized activation of tyrosine kinase, phosphatidylinositol 3‐kinase, and phospholipase D ( Rivard et al , 1994 ; Tsunoda & Owyang, 1995), while occupancy of low‐affinity receptors induces activation of phospholipase C and enhanced phosphoinositide breakdown ( Bianchi et al , 1994 ; Tsunoda et al , 1996 ). Whereas CCK 1 receptors in the pancreas are present in both high‐ and low‐affinity states, those in gastrointestinal smooth muscle exist only in the low‐affinity state ( Maubach et al , 1991 ; Taniguchi et al , 1995 ; Varga et al , 1998 ; Kisfalvi et al , 2001 ) and mediate CCK‐induced contraction (Figure 6). In line with these results, Moran et al (1994) suggested that CCK‐8 induces pyloric contraction and delays gastric emptying via interaction with receptors functionally similar to low‐affinity pancreatic receptors.…”

Interactions between cholecystokinin and opioids in the isolated guinea‐pig ileum

“…Hence, CCK‐8‐induced tonic contracture and κ‐opioid system activation may be mainly mediated through different CCK A receptor affinity states. The data of Singh and co‐workers (1995) suggest that the CCK A antagonist used in our study, PD‐140,548, may interact preferentially with the high‐affinity CCK A receptor state, because the antagonist inhibited the CCK‐8‐induced contraction of guinea‐pig gallbladder – a response probably mediated by the low‐affinity state of CCK A receptor ( Taniguchi et al ., 1995 ) – with a functional affinity 30 fold lower than its binding affinity in the pancreas, where the high affinity state predominates ( Taniguchi et al ., 1995 ). Therefore, it is possible that PD‐140,548 antagonised the tonic GPI contraction to CCK‐8 at lower concentrations than those inhibiting the κ‐activation because: (i) the two CCK‐8 effects are mainly mediated through different CCK A receptor affinity states; and, (ii) the CCK A antagonist preferentially occupied the affinity state mediating the tonic response.…”

Different actions of CCK on pancreatic and gastric growth in the rat: effect of CCKA receptor blockade

“…Although the nucleotide sequence of cloned cDNAs is identical (de Weerth et al , 1993), affinity states of CCK A ‐receptors on pancreas and GI smooth muscle (e.g. gallbladder) are different and can be distinguished by the CCK‐analogue, JMV‐180 (Maubach et al , 1991; Taniguchi et al , 1995). Indeed, whereas CCK A ‐receptors in the pancreas are present in both high and low affinity states, those on GI smooth muscle only exist in the low affinity state (Maubach et al , 1991; Taniguchi et al , 1995) and mediate CCK‐induced contraction.…”