Brain CCK receptors: Species differences in regional distribution and selectivity

Williams, John A.; Gryson, Karen A.; McChesney, Dennis J.

doi:10.1016/0196-9781(86)90228-7

Cited by 44 publications

(4 citation statements)

References 16 publications

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“…The diverse physiological functions of CCK and its receptors in adult brain, prompted us to investigate whether they also played a role during development. We sought to determine the mRNA expression of the two receptors, as all previous studies of CCK receptor distribution were based on binding assays [ 13 – 18 ]. Contrary to its being considered the peripheral receptor, we discovered robust and widespread expression of Cckar mRNA in the developing brain by in situ hybridization from at least embryonic day (E) 13.5 onward, whereas Cckbr transcripts were not detected until late embryonic stages ( Fig 1A and 1B ).…”

Section: Resultsmentioning

confidence: 99%

“…CCKAR is the peripheral receptor, having limited expression in the brain [ 9 , 10 ], whereas CCKBR predominates in the CNS, mostly in neocortical and limbic structures; in the periphery, it is restricted to the stomach, where it serves as a receptor for gastrin, a hormone homologous to CCK [ 9 , 11 , 12 ]. In brain, CCKAR and CCKBR have distinct distribution and selectivity in different rodent species, as suggested by binding assays of radiolabeled CCK peptides [ 13 – 18 ]. CCK is expressed in neocortical pyramidal neurons, including corticocortical projection neurons [ 19 – 22 ] and in a distinct subtype of interneurons [ 23 – 29 ].…”

Section: Introductionmentioning

confidence: 99%

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Functional Synergy between Cholecystokinin Receptors CCKAR and CCKBR in Mammalian Brain Development

et al. 2015

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Cholecystokinin (CCK), a peptide hormone and one of the most abundant neuropeptides in vertebrate brain, mediates its actions via two G-protein coupled receptors, CCKAR and CCKBR, respectively active in peripheral organs and the central nervous system. Here, we demonstrate that the CCK receptors have a dynamic and largely reciprocal expression in embryonic and postnatal brain. Using compound homozygous mutant mice lacking the activity of both CCK receptors, we uncover their additive, functionally synergistic effects in brain development and demonstrate that CCK receptor loss leads to abnormalities of cortical development, including defects in the formation of the midline and corpus callosum, and cortical interneuron migration. Using comparative transcriptome analysis of embryonic neocortex, we define the molecular mechanisms underlying these defects. Thus we demonstrate a developmental, hitherto unappreciated, role of the two CCK receptors in mammalian neocortical development.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Functional Synergy between Cholecystokinin Receptors CCKAR and CCKBR in Mammalian Brain Development

et al. 2015

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“…Such data makes it tempting to suggest that small non-sulphated, CCK peptides containing the active site of the hormones (Trp-Met-Asp-Phe-NH2) are autocrine regulators of thyroid C-cells. Along this line of reasoning, the data also suggest that C-cell membranes are equipped with CCK receptors of the brain type (CCK B-receptors), which in contrast to the gall-bladder-and pancreastype CCK-receptor (CCK A-receptor) do not require tyrosine sulphation of the ligand (Williams, Gryson & McChesney, 1986).…”

Section: <¡ ( 2 ' Omentioning

confidence: 95%

Non-sulphated cholecystokinin in human medullary thyroid carcinomas

Rehfeld¹,

Johnsen²,

Ødum³

et al. 1990

Journal of Endocrinology

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The expression of gastrin/cholecystokinin (CCK) peptides and their precursors was examined in 16 medullary carcinomas of the human thyroid. Measurements with libraries of sequence-specific radioimmunoassays before and after enzymatic cleavage of extracts and chromatographic fractions showed that the carcinomas contained 1.7 pmol carboxyamidated CCK/g tissue (median; range 0.6-21.8 pmol/g), 0.9 pmol glycine-extended precursor/g (median; range less than 0.2-2.3 pmol/g) and 2.3 pmol further COOH-terminal-extended proCCK/g (median; range 0.9-6.2 pmol/g). Neither carboxyamidated gastrins nor any progastrins could be measured. Gel and reverse-phase chromatography revealed only small molecular forms, i.e. greater than 90% of the amidated immunoreactivity eluted like non-sulphated CCK-8 or CCK-7. The results show that human medullary thyroid carcinomas synthesize CCK peptides. The predominance of non-sulphated CCK is unusual. Taken together with earlier observations from dogs and pigs, our results raise the possibility that small non-sulphated CCK peptides modulate thyroid C-cell secretion in an autocrine manner.

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“…However, the gastrin gene is not expressed in the cerebral cortex (19), and brain receptors for CCK fragments are distinctly different from the receptors for the same fragments in the pancreas and gallbladder (22). Our interest in C-terminal CCK fragments was stimulated by reports (23) that these fragments possess potent anticonvulsant activity in several chemical convulsant models, including picrotoxin-induced seizures.…”

Section: The Cholecystokinins: Endogenous Anticonvulsant Peptides?mentioning

confidence: 96%

Theoretical conformational analysis of peptides. Evolution of a strategy and its application to cholecystokinin analogs

Wolfe¹,

Bruder²,

Weaver³

et al. 1988

Can. J. Chem.

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. Can. J. Chem. 66,2703Chem. 66, (1988. Scheraga's ECEPP program has been used to determine the relationship between one-point energies and the energies minimized by a quadratic procedure, for different sized (+, +, x ,) dihedral angle grid searches of simple peptides. Based on these trials, a new subroutine, INIT, has been written and incorporated into the program. This subroutine calculates the one-point ECEPP energies of up to 200,000 random permutations of (4, +) = 0, + 90, 180 and (X ,) = -60, 180 with all w = X,] = 180; after each 40,000 permutations, the structures having the 10 lowest energies are ordered and selected for minimization. The ECEPP program has been modified further to provide an MMP2(85) input file as part of its normal output. This allows structures located by INIT to be minimized automatically, and then refined by the Newton-Raphson minimization and MMPEP parameters of MMP2(85).During the development of this protocol, it has been found that MMPEP correctly reproduces the C7 conformational preference of the alanyl dipeptide in nonpolar media, and also the experimentally observed shift to a~ and PII conformations in polar solvents, when the dielectric constant E = 78.5 D. This dielectric constant has, therefore, been selected for a conformational analysis, using INITIMMPEP, of the peptides Gly-Trp-Met-Asp-Phe-NH2 (GLMAP), Gly-D-Trp-Met-Asp-Phe-NH2 (GDMAP), and Gly-Gly-Met-Asp-Phe-NH2 (GGMAP); GLMAP is CCK-5, a cholecystokinin fragment possessing anticonvulsant activity, which is found in the brain. The analogs GDMAP and GGMAP are not active, or much less so than GLMAP. One strongly preferred structure has been found, in each case, for GLMAP (GLMAP3) and GDMAP (GDMAP39). These structures are very similar, in the nature of the edge-to-face stacking of their Trp and Phe aromatic rings, but the C-terminal regions differ. The conformation of the C-terminal tetrapeptide of GLMAP3 is identical to a previously calculated structure of CCK-4. A comparison of the C-terminal regions of GLMAP3 and GDMAP39 with the structure of 5,5-diphenylhydantoin suggests that the mechanisms of anticonvulsant action of phenytoin and CCK-5 are not the same. In the absence of an aromatic-aromatic interaction, no clear-cut conformational preference is found for GGMAP. The structure of GGMAP whose C-terminal region is the same as that of GLMAP3 (GGMAP20) is 1.51 kcal/mol higher in energy than the lowest energy structure, and lacks the hydrophobic wall provided by the Trp residue of GLMAP3. Au cours du dtveloppement de ce protocole, on a trouvt que MMPEP reproduit correctement la preference conformationnelle du C7 du dipeptide de l'alanyle dans des milieux non-polaues ainsi que le dtplacement observt exptrimentalement vers les conformations c i~ et PI1 dans des solvants polaires, lorsque E = 78,5 D. On a donc choisi cette constante ditlectrique pour une analyse conformationnelle, utilisant le programme INITIMMPEP, des peptides Gly-Trp-Met-Asp-Phe-NH2 (GLMAP), Gly-D-Trp-Met-Asp-Phe-NH2 (GDMAP) et Gly-Gly-Met-Asp-Phe-NH2 (...

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Brain CCK receptors: Species differences in regional distribution and selectivity

Cited by 44 publications

References 16 publications

Functional Synergy between Cholecystokinin Receptors CCKAR and CCKBR in Mammalian Brain Development

Functional Synergy between Cholecystokinin Receptors CCKAR and CCKBR in Mammalian Brain Development

Non-sulphated cholecystokinin in human medullary thyroid carcinomas

Theoretical conformational analysis of peptides. Evolution of a strategy and its application to cholecystokinin analogs

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