Article Figures & Data
Figures
- Figure 1
Predicted structure of human preprocholecystokinin. The signal peptide consists of residues −20 to −1. The amino terminal flanking peptide consists of residues 1 to 25. The largest characterized form from brain and intestine, CCK-58, consists of residues 26 to 83. Other active molecular forms are derived from this precursor, such as CCK-39, CCK-33, CCK-22, CCK-7, and CCK-5.
- Figure 2
Schematic representation of the rat CCK1 receptor showing the postulated transmembrane topology, sites for putative NH2-linked glycosylation (tridents), serine and threonine phosphorylation by PKC and protein kinase A (PO3), and conserved cysteines in the first and second ECLs, possibly forming a disulfide bridge, and a possible palmitoylated conserved cysteine in the cytoplasmic tail. NH2—, N terminus; COOH—, C terminus.
- Figure 3
Schematic representation of the rat CCK2 receptor showing the postulated transmembrane topology, sites for putative NH2-linked glycosylation (tridents), serine and threonine phosphorylation by PKC and protein kinase A (PO3), and conserved cysteines in the first and second ECLs, possibly forming a disulfide bridge, and a possible palmitoylated conserved cysteine in the cytoplasmic tail. NH2—, N terminus; COOH—, C terminus.
- Figure 4
Schematic representation of genes encoding human CCK1 and CCK2 receptors. Shown are position and size of the exons (shaded boxes) and introns (lines) comprising the genes for the CCK1 and the CCK2 receptors; smaller arabic numbers represent size of each exon and intron in base pairs. Roman numerals refer to putative transmembrane-spanning regions encoded within each exon. ATG and TGA, putative start and stop codons, respectively. CCK2 receptor gene: the second splice variant (short form) differs only in the size of exon 4, in which a sequence is absent compared with long form, corresponding to a block of five amino acids within the third intracellular loop. The third splice variant encodes an N-terminally truncated receptor. The gene structure is similar, except that there is an alternative first exon (exon 1b) that makes up the 5′ untranslated region of this truncated receptor.
- Figure 5
Autoradiograms showing the distribution of [3H]BDNL binding to CCK1 and CCK2receptors in the rat forebrain and midbrain. Moderate to high densities of receptors are observed in the olfactory bulbs (A), the anterior olfactory nucleus (B), the neocortex, and especially in layer III of the medial frontal (B–C) and cingulate (E–I) cortices, the layer IV of frontal (B and C) and frontoparietal (D–J) cortices, the layers II–IV of retrosplenial cortex (L), the olfactory tubercle (E–I), the endopiriform nucleus (E–K), the nucleus accumbens (D–F), the striatum (D–I), and the hippocampus, where CCK receptors are more concentrated in the dentate gyrus and subiculum (K). [3H]BDNL, Boc-Tyr(SO3H)-[43H]Nle-Gly-Trp-[43H]Nle-Asp-Phe-NH2.
- Figure 6
Schematic representation of the mechanism of action of CCK in the regulation of feeding behavior. It is proposed that CCK from the intestine is delivered, after a meal, in the circulation to the stomach, where it acts directly on vagal afferents to transmit sensations of fullness to the brain. NTS, nucleus tractus solitarius; PVN, paraventricular nucleus; PBN, parabrachial nucleus; VMH, ventromedial nucleus of the hypothalamus (reproduced from Dockray, 1988).
- Figure 7
Effects of i.p. injection of BDNL, BC 197, and BC 264 administered 30 min before the experiment in the elevated plus-maze. The behavioral responses of rats were measured in the elevated plus-maze for 5 min. They are expressed as the percentage ± S.E.M. of time spent in open arms. ★ P< .05 and ★★ P < .01 compared with control group.
- Figure 8
Prevention of the effects of L-365,260 (1 mg/kg i.p.) by the selective dopamine D1 receptor antagonist SCH-23390 (0.07 mg/kg s.c.) or the dopamine D2 receptor antagonist sulpiride (25 mg/kg s.c.) in the forced-swim test in mice.★ P < .05 compared with the control group; ⋆ P < .05 compared with the same dose of L-365,260 without antagonists (Newmann-Keuls test).
- Figure 9
Effects of the selective CCK2 receptor agonists BC 264 and BC 197 on working memory in a two-trial task in the Y maze. In the first trial (acquisition phase), one arm of the maze was closed and the rats were allowed to visit the other two arms for 3 min. During the second trial (retrieval phase), rats had free access to the three arms for 3 min. When the two trials were separated by a 2-h time interval, recognition memory allowed the control rats to spend more time in the novel arm. When the two trials were separated by a 6-h time interval, recognition memory was lost, and the control rats spent approximately the same time in the three arms of the maze. BC 264 or BC 197 was injected i.p. 30 min before the second trial (restitution phase). The CCK2 receptor antagonist L365,260 was injected i.p. 60 min before the experiment. The results are expressed as mean ± S.E. of the percentage of time spent in the novel arm.★ P < .05 compared with control;⋆ P < .05 and⋆⋆ P < .01 compared with CCK2 receptor agonist alone (Duncan test).
- Figure 10
Hypothetical model of the supraspinal interactions between CCK, via CCK1 and CCK2receptors, and the opioid system via δ (OP1)-opioid and μ (OP3)-opioid receptors. CCK receptor agonists, endogenous or exogenous, stimulate CCK2 and/or CCK1 receptors, which can modulate the opioidergic (enkephalinergic) systems either directly (via the binding of opioid agonists or via C-fiber evoked activity) or indirectly (via the release of endogenous enkephalins). In addition, activation of μ (OP3)-opioid receptors, which leads to antinociceptive responses, can negatively modulate the release of endogenous CCK, whereas δ (OP1)-opioid receptor activation may enhance it.
- Figure 11
Conditioned suppression of motility test in mice. Effects of the CCK1 and CCK2 receptor antagonists L-364,718 and L-365,260, respectively, on the antidepressant-like effects induced by i.v. injected RB 101. Mice were placed in a transparent rectangular cage with a metallic grid floor. Animal displacements were measured by drawing squares on the floor for counting. On the first day, the mouse was left in the test cage for 6 min and received electric footshocks. On the second day, the mouse was placed in the same cage without receiving electric footshocks, and motility changes were tested by counting the number of squares crossed, plus the number of rearings in 6 min. The mice belonging to the control group were handled in the same way as those in the conditioned suppression group except that they did not receive electric footshocks on the first day. ★★ P < .01 compared with control group; ⋆ P < .05 and ⋆⋆ P < .01 compared with the same dose of RB 101 without antagonist.
Tables
Antagonist Ki Selectivity CCK2/CCK1 Reference CCK1 CCK2 nM L-364,718 0.1 375 3,750 Evans et al. (1986) SR-27897 0.2 160 800 Gully et al. (1993) IQM-93,333 0.6 >5,000 >8,000 Martin-Martinez et al. (1997) PD-140,548 2.83-a 2603-a 93 Boden et al. (1993) FK-480 0.43-a 723-a 180 Ito et al. (1994a) 2-NAP 250 70,000 300 Hull et al. (1993) T-0632 0.24 5,600 23,000 Taniguchi et al. (1996) TP-680 1.2 1,812 1,510 Akiyama et al. (1996) -
↵3-a IC50 value.
-
Antagonist Ki Selectivity CCK1/CCK2 Reference CCK1 CCK2 nM L-365,260 800 7 115 Lotti and Chang (1989) PD-134,308 1,440 0.9 1,600 Horwell et al. (1991) LY-288,513 11,600 31 370 Howbert et al. (1992) RP-73,870 1,634 0.5 3,300 Pendley et al. (1995) YM-022 150 0.1 1,500 Nishida et al. (1994) RB-210 1,518 14 110 Blommaert et al. (1993) CP-212,454 180 0.5 360 Lowe et al. (1995) L-740,093 1,600 0.1 16,000 Patel et al. (1994) YF-476 1137-a 0.27-a 565 Semple et al. (1997) CI-1015 2,900 3 967 Trivedi et al. (1998) -
↵7-a IC50 value.
-
Boc-D.Asp-Tyr(SO3H)-Nle-D.Lys-Trp-Nle-Asp-Phe-NH2 BC 197 Boc-Tyr(SO3H)-gNle-mGly-Trp-NMe(Nle)-Asp-Phe-NH2 BC 264 HOOC-CH2-CO-Trp-NMe(Nle)-Asp-Phe-NH2 RB 400 Asp-Tyr(SO3H)-(NMe)Nle-Gly-Trp-(NMe)Nle-Asp-Phe-NH2 SNF-8702 Boc-γD-Glu-Tyr(SO3H)-Nle-D.Lys-Trp-Nle-Asp-Phe-NH2 BC 254 Agonist Ki Selectivity CCK1/CCK2 Reference CCK1 CCK2 nM BC 197 2900 150 20 Charpentier et al. (1989) BC 264 78 0.1 780 Charpentier et al. (1988b) RB 400 >3000 0.42 >7000 Million et al. (1997) SNF-8702 3800 0.9 4000 Knapp et al. (1990) BC 254 2500 0.56 4500 Charpentier et al. (1989) Frontal cortex Septal region Layers I–III ++ Septum + Layer III, medial part ++++ Bed nucleus of the stria terminalis ++ Layer IV +++ Septohippocampal nucleus ++ Layer V ++ Hippocampus Layer VI +++ Subiculum +++ Frontoparietal motor cortex CA1–CA3 + Layers I–III ++ Dentate gyrus +++ Layer IV +++ Amygdala Layers V, VI ++ Lateral nucleus ++ Frontoparietal somatosensory cortex Posteromedial nucleus ++ Layers I–III ++ Amygdalo-hippocampal area ++ Layer IV +++ Hypothalamus Layers V, VI ++ Ventromedial nucleus +++ Striate cortex Paraventricular nucleus +++ Layers I–V +++ Supraoptic nucleus +++ Temporal cortex (auditory area) Thalamus Layers I–III +++ Lateral habenula + Layer IV ++++ Paraventricular nucleus ++ Layers V, VI +++ Reticular thalamic nucleus +++ Zona incerta + Cingulate cortex, layer III ++++ Midbrain Retrosplenial cortex ++++ Superior ++ Entorhinal cortex +++ Substantia nigra ++ Endopyriform nucleus ++++ Periacqueductal gray matter + Olfactory-system Olfactory bulbs External plexiform layer +++ Glomerular layer +++ Anterior olfactory nucleus ++ Olfactory tubercule +++ Primary olfactory cortex (superficial layer) ++++ Basal ganglia Striatum Head +++ Body +++ Tail + Nucleus accumbens Anterior part ++++ Posterior part + Globus pallidus + -
++++, high level; +++, moderate level; ++, low level; +, very low level.
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In this issue
Jump to section
- Article
- I. Introduction
- II. Characterization of Cholecystokinin (CCK) Receptors
- III. Molecular Biology of CCK Receptors
- IV. Receptor Structure/Function Studies
- V. Radioligands and Binding Assays: Heterogeneity of CCK1 and CCK2 Receptors
- VI. Distribution of CCK Receptors
- VII. Physiological Implications of CCK Receptors
- VIII. Conclusion
- Acknowledgments
- Footnotes
- Abbreviations
- References
- Figures & Data
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