Functional and molecular characterization of CCK receptors in the rat pancreatic acinar cell line AR 4-2J

Lambert, Monique; Bui, Ngoc Diem; Christophe, Jean

doi:10.1016/0167-0115(91)90043-g

Cited by 32 publications

(14 citation statements)

References 22 publications

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“…In previous studies, ornithine decarboxylase activity, or 3H-thymidine or 75Se-selenomethionine incorporation were used as indices of responsiveness of AR4-2J cells to gastrin (Scemama et al, 1989;Seva et al, 1990;Watson et al, 1991a). Interpretation of data obtained by the latter approach is frustrated by the fact that gastrin increases secretion, and presumably synthesis, of proteins such as the enzyme amylase from AR4-2J cells (Lambert et al, 1991).…”

Section: Discussionmentioning

confidence: 99%

“…The AR4-2J rat pancreatic tumour cell line has been advocated for studies of gastrin receptors. AR4-2J cells express both CCK-A, coupled to stimulation of pancreatic enzyme secretion, and gastrin/CCK-B receptors (Scemama et al, 1989;Lambert et al, 1991). A trophic response to gastrin has been shown in these cells which is coupled to the gastrin/CCK-B receptor type (Scemama et al, 1989 …”

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confidence: 99%

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Autocrine stimulation of growth of AR4-2J rat pancreatic tumour cells by gastrin

Blackmore

Bh²

1992

Br J Cancer

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Summary The control of cell proliferation by gastrin has been investigated in a rat pancreatic tumour cell line, AR4-2J. Exogenous gastrin, 10-12 to 10-8 M, stimulated cell growth of thymidine-synchronised AR4-2J cells cultured over 48 h in serum-free medium. Cell lysates of AR4-2J cells contained an average of 4.5 and 3.5 pg gastrin per 106 cells, when grown in serum-supplemented or serum-free media, respectively, as revealed by radioimmunoassay. In serum-free medium, AR4-2J secrete 34ngl 10-6 cells of gastrin over 48h. Addition of an anti-gastrin immunoglobulin preparation, but not control immunoglobulins, caused a maximum 52% reduction in cell growth. These data are consistent with an autocrine role for gastrin in the control of AR4-2J cell growth. These results were supported by studies with gastrin/CCK receptor antagonists. Six non-peptide gastrin/CCK receptor antagonists inhibited AR4-2J cell growth in a concentration-related manner. The concentration required for 50% inhibition (IC50) of cell growth by the amino acid-derived antagonists proglumide (3.5 x 10-M), benzotript (1.8 x 10-3 M), loxiglumide (1.1 x 10-4 M) and lorglumide (6.7 x 10-5 M) were of the same order and significantly correlated with their IC50 for inhibition of 1251-gastrin binding to AR4-2J cells. Inhibition of cell growth by these antagonists was partially reversed by the addition of exogenous gastrin. In contrast, the ICm for inhibition of cell growth with two benzodiazepine-derived antagonists, the CCK-B receptor antagonist L-365,260 (4.6 x 10-5 M) and the CCK-A receptor antagonist devazepide (1.7 x 10-' M) were two-three orders of magnitude greater than those required to inhibit gastrin binding (10-8-10-7 M). The growth inhibitory effects of L-365,260 and devazepide were not reversed by exogenous gastrin suggesting these benzodiazepine-derived antagonists do not inhibit cell growth by interaction with gastrin receptors. The results are consistent with gastrin being an autocrine growth factor in AR4-2J cells, and that stimulation of cell growth is due to stimulation of the gastrin, rather than CCK-B, receptor sub-type. This study highlights that gastrin receptor antagonists warrant further investigation as agents to control growth of tumours, such as those from the gastrointestinal tract, which express gastrin receptors.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Autocrine stimulation of growth of AR4-2J rat pancreatic tumour cells by gastrin

Blackmore

Bh²

1992

Br J Cancer

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“…The same cell line was later found to possess 75 % CCK-A receptors and 25 % CCK-B receptors [229]. In another study, 80% of receptors were CCK-B [230]. Functional studies at different stages of evolution of the cell line AR4-2J indicate that both CCK-A and CCK-B receptors can mediate CCK and gastrin-induced enzyme secretion [228 -2301.…”

Section: The Cck-b Receptor In the Normal Pancreas And The Ar4-2j Celmentioning

confidence: 99%

“…Functional studies at different stages of evolution of the cell line AR4-2J indicate that both CCK-A and CCK-B receptors can mediate CCK and gastrin-induced enzyme secretion [228 -2301. Coupling of the CCK-B receptor to guanine-nucleotide-binding regulatory proteins G, and G, has been reported [230]. Interestingly, CCK-B receptor occupancy by agonists induces inhibition of adenylate cyclase, even though this signalling pathway is not observed with the CCK-A receptor in the normal pancreas [231].…”

Section: The Cck-b Receptor In the Normal Pancreas And The Ar4-2j Celmentioning

confidence: 99%

The peripheral cholecystokinin receptors

Silvente-Poirot

Dufresne

Vaysse

et al. 1993

European Journal of Biochemistry

125

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“…CCK agonists and antagonists acting at central CCKB receptors respectively block and enhance opiate-induced analgesia (13). CCKB-type receptors have also been described outside the CNS in gastrointestinal smooth muscle cells (14), where they modulate gallbladder and bowel motility; and in guinea pig (15) and dog pancreas (16) and various neoplastic tissues [such as human stomach, colon (17), and lung carcinomas (18), and the rat pancreatic acinar carcinoma cell line AR42-J (19)], where they may regulate cell growth. The presence of CCKB receptors on peripheral lymphocytes and monocytes and monocyte-derived splenic cells suggests that CCK may play a role in the long-suspected neuroendocrine modulation of the immune system (20,21).…”

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confidence: 99%

Brain and gastrointestinal cholecystokinin receptor family: structure and functional expression.

Wank

Pisegna

Weerth

1992

Proc. Natl. Acad. Sci. U.S.A.

374

111

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Cholecystokinin was one of the first gastrointestinal peptides discovered in the mammalian brain. In the central nervous system there is evidence for CCKA and CCKB receptor subtypes. The CCKA receptors occur in a few localized areas of the central and peripheral nervous systems where they modulate feeding and dopamine-induced behavior. CCKB receptors occur throughout the central nervous system where they modulate anxiety, analgesia, arousal, and neuroleptic activity. We have recently purified and cloned a CCKA receptor cDNA from rat pancreas that allowed isolation of an identical cDNA from rat brain by using the polymerase chain reaction. Using low-stringency hybridization screening of cDNA libraries from rat brain and AR42-J cells, which possess large numbers of CCKB receptors, we identified previously unreported cDNAs, the sequence of which were identical in both tissues. The cDNA sequence encodes a 452-amino acid protein that is 48% identical to the CCKA receptor and contains seven transmembrane domains characteristic of guanine nucleotide-binding regulatory protein-coupled receptors. COS-7 cells transfected with this cDNA expressed binding sites for agonists and antagonists characteristic of a CCKB receptor subtype. We conclude that this cDNA isolated from rat brain and AR42-J cells is a receptor of the CCKB subtype and that the respective cDNAs for both CCKA and CCKB are identical in the brain and gastrointestinal system. The cholecystokinin (CCK) family of peptides was originally isolated from the mammalian gastrointestinal tract (1) and was one of the first gastrointestinal peptides to be discovered in the brain (2, 3), where the predominant molecular form, cholecystokinin octapeptide (CCK-8), exists in sulfated and desulfated forms (2, 4).The receptors for CCK in both the central nervous system (CNS) and peripheral tissues can be classified into two subtypes, CCKA and CCKB, on the basis of their affinity (i) for a structurally and functionally related family of peptides with identical COOH-terminal pentapeptide sequences and differing sulfation at the sixth (gastrin) and seventh (CCK) tyrosyl residues and (ii) for specific antagonists. CCKA receptors are highly selective (500-to 1000-fold higher affinity) for sulfated analogues and the antagonist L-364,718, whereas CCKB receptors have similarly high affinity for both sulfated and nonsulfated peptide analogues (only a 3-to 10-fold higher affinity for sulfated peptide analogues) and the antagonist L-365,260 (5-8).A CCKA receptor subtype predominates in the gastrointestinal system but occurs also in highly localized areas of the rat CNS, where it modulates feeding and dopamine-induced behavior (9-11). We recently purified the CCKA receptor and cloned its cDNA from rat pancreas (12). This cDNA did not hybridize to poly(A)+ RNA from rat brain on Northern blot analysis, which raised the possibility that the rat brain CCK receptor with a CCKA receptor-subtype pharmacology was different from the rat pancreatic CCKA receptor (12).The CCKB receptor subtype...

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Functional and molecular characterization of CCK receptors in the rat pancreatic acinar cell line AR 4-2J

Cited by 32 publications

References 22 publications

Autocrine stimulation of growth of AR4-2J rat pancreatic tumour cells by gastrin

Autocrine stimulation of growth of AR4-2J rat pancreatic tumour cells by gastrin

The peripheral cholecystokinin receptors

Brain and gastrointestinal cholecystokinin receptor family: structure and functional expression.

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