Molecular Models for Cholecystokinin‐A Receptor

Dawson, Eric S.; Henne, Randel M.; Miller, Laurence J.; Lybrand, Terry P.

doi:10.1034/j.1600-0773.2002.910605.x

Cited by 15 publications

(17 citation statements)

References 73 publications

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“…This set of data strongly supports differences in conformation of these two closely related receptors. This is also consistent with the distinct modes of docking the same CCK peptides to both receptors that has been proposed previously (Dawson et al, 2002;Miller and Gao, 2008).…”

Section: Allosteric Cck1r Antagonist Radioligandsupporting

confidence: 77%

Development of a Highly Selective Allosteric Antagonist Radioligand for the Type 1 Cholecystokinin Receptor and Elucidation of Its Molecular Basis of Binding

Dong

Vattelana

Lam

et al. 2015

Molecular Pharmacology

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Section: Allosteric Cck1r Antagonist Radioligandsupporting

confidence: 77%

Development of a Highly Selective Allosteric Antagonist Radioligand for the Type 1 Cholecystokinin Receptor and Elucidation of Its Molecular Basis of Binding

Dong

Vattelana

Lam

et al. 2015

Molecular Pharmacology

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“…Like other members of the G-protein-coupled receptor superfamily, CCK1R has a heptahelical transmembrane (TM) structure (4,24,91,143) (Fig. 3).…”

Section: Cck Receptor In Different Animal Speciesmentioning

confidence: 99%

How does cholecystokinin stimulate exocrine pancreatic secretion? From birds, rodents, to humans

Wang¹,

Cui²

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Wang BJ, Cui ZJ. How does cholecystokinin stimulate exocrine pancreatic secretion? From birds, rodents, to humans. Am J Physiol Regul Integr Comp Physiol 292: R666-R678, 2007. First published October 19, 2006; doi:10.1152/ajpregu.00131.2006.-The field of cholecystokinin (CCK) stimulation of exocrine pancreatic secretion has experienced major changes in the recent past. This review attempts to summarize the present status of the field. CCK production in the intestinal I cells, the molecular forms of CCK produced and subsequently circulated in the blood, the presence or absence of CCK receptors on the isolated pancreatic acinar cells and the associated signaling for acinar cell secretion, and the actual circuits and sites of action for CCK regulation of exocrine pancreatic secretion in vivo are reviewed in different animal species with an emphasis on birds, rodents, and humans. Clear differences in the relative importance of neural and direct modes of CCK action on pancreatic acinar cells were identified. Rodents seem to be endowed with both modes of action, whereas in humans the neural mode may predominate. In birds, such as duck, the direct mode needs further assistance from pituitary adenylate cyclaseactivating peptide/VIP receptors. However, much further work needs to be directed to the neural mode to map out all sites of CCK action and details of the full circuits, and we foresee a major revival for this field of research in the near future. pancreatic acinar cells; vagal afferent nerves; plasma cholecystokinin concentration; species specificity IT IS GENERALLY ACCEPTED THAT cholecystokinin (CCK) as a gut hormone is an important endogenous secretagogue in exocrine pancreatic secretion. CCK also stimulates gallbladder contraction and enhances growth of the exocrine pancreas (63,115,138). CCK is produced and released by the intestinal mucosal I cells (78). This source of CCK may travel through the circulation to target tissues that include the exocrine pancreas and gallbladder (65,78). CCK peptides are also found in large quantities in neurons, but neuronal CCK contributes negligibly to CCK concentration in the circulation (118). This general picture has been changed drastically by the recent findings that CCK can also stimulate exocrine pancreatic secretion by the excitation of sensory nerves and vagovagal and enteropancreatic reflexes, and this may be the only pathway in humans (65, 105). In addition, major differences have been found in the traditional humoral pathway, depending on the animal species (35,149). Therefore, the purpose of this review is to present the current status of CCK regulation of exocrine pancreatic secretion with a particular emphasis on species specificity as shown in birds, rodents, and humans.

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“…We previously employed this biophysical approach to evaluate the environment of Alexa within a CCK-8-like analogue, Alexa 488 -Gly-[(Nle 28,31 )CCK-26 -33] (CCK-8 probe), bound to the type A CCK receptor (1). Our data demonstrated that conformational changes associated with activation of that receptor cause the amino terminus of bound CCK to move into an aqueous milieu from its more protected environment.…”

mentioning

confidence: 99%

Distinct Molecular Mechanisms for Agonist Peptide Binding to Types A and B Cholecystokinin Receptors Demonstrated Using Fluorescence Spectroscopy

Harikumar

Clain

Pinon

et al. 2005

Journal of Biological Chemistry

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Understanding of the molecular basis of agonist ligand binding to a receptor and the conformational changes in that receptor that occur during its activation are key insights that should be helpful for the rational design and refinement of receptoractive drugs. The type A and type B cholecystokinin (CCK) 1 receptors are structurally related members of the rhodopsin/␤-adrenergic receptor family of G protein-coupled receptors that are activated by natural peptide ligands that are also structurally related to each other (2, 3). Of interest, each of these receptors has distinct structural specificity for its activation, with CCK-8 binding with high affinity and acting as a potent agonist of both receptors, whereas CCK-4 has similar action only at the type B CCK receptor, with very low affinity and biological activity at the type A CCK receptor (4). Insights into the molecular basis of ligand binding to each of this pair of receptors provide an opportunity to better understand the evolution of their differences in structural specificity.Fluorescence spectroscopy is a versatile and powerful technique that can provide information about the environment of a fluorophore within a bound ligand as well as the conformational changes in a receptor that occur upon activation. We previously employed this biophysical approach to evaluate the environment of Alexa within a CCK-8-like analogue, Alexa 488 -Gly- [(Nle 28,31 )CCK-26 -33] (CCK-8 probe), bound to the type A CCK receptor (1). Our data demonstrated that conformational changes associated with activation of that receptor cause the amino terminus of bound CCK to move into an aqueous milieu from its more protected environment.In the current study, we have focused on the type B CCK receptor, utilizing the same CCK-8-like fluorescent probe as well as developing and studying an additional probe with its fluorophore situated closer to the pharmacophoric domain of the natural peptide ligand of the type B CCK receptor (Alexa 488 -Trp-Nle-Asp-Phe-NH 2 ; CCK-4 probe) (1). We have characterized the type B CCK receptor binding and biological activity of both of these probes. We have also measured the fluorescence anisotropy, lifetime, and ability to quench each of these probes when bound to this receptor. By manipulating the G protein-binding interface of this receptor, we also gained insights into the conformational changes associated with its active and inactive conformational states.Our results demonstrate that the fluorescent CCK-8 probe and the fluorescent CCK-4 probe were each able to bind specifically and with high affinity to the type B CCK receptor. They were full agonists at this receptor, able to elicit full intracellular calcium responses. Like the CCK-8 probe studied at the type A CCK receptor, both of these probes exhibited shorter lifetimes and lower anisotropy when the type B CCK receptor was in the active conformation than when it was shifted to its inactive, lower affinity, G protein-uncoupled state using guanosine 5Ј-[␤,␥-imido]triphosphate trisodium salt (GppNHp). ...

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Molecular Models for Cholecystokinin‐A Receptor

Cited by 15 publications

References 73 publications

Development of a Highly Selective Allosteric Antagonist Radioligand for the Type 1 Cholecystokinin Receptor and Elucidation of Its Molecular Basis of Binding

Development of a Highly Selective Allosteric Antagonist Radioligand for the Type 1 Cholecystokinin Receptor and Elucidation of Its Molecular Basis of Binding

How does cholecystokinin stimulate exocrine pancreatic secretion? From birds, rodents, to humans

Distinct Molecular Mechanisms for Agonist Peptide Binding to Types A and B Cholecystokinin Receptors Demonstrated Using Fluorescence Spectroscopy

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